Back to resultsA Study of ARGX-110 in Combination With Azacytidine in Participants With Newly Diagnosed Acute Myeloid Leukemia (AML) or High Risk Myelodysplatic Syndrome (MDS)
Primary Purpose
Leukemia, Myeloid, Acute, Myelodysplastic Syndromes
Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
ARGX-110
AZA
Sponsored by
About this trial
This is an interventional treatment trial for Leukemia, Myeloid, Acute
Eligibility Criteria
Inclusion Criteria:
- Signed informed consent form (ICF) indicating an understanding of the purposes, risks, and procedures required for the study and willingness and ability to participate in the study
- Acute myeloid leukemia (AML) or high risk myelodysplastic syndrome (MDS) (according to 2016 World Health Organization [WHO] classification definition of greater than or equal to [>=] 20 percent [%] blasts) (bone marrow) unsuitable for intensive treatment (including stem cell transplantation) with a curative intent, but eligible to receive azacytidine (AZA) treatment
- Expected life expectancy >= 3 months, at the discretion of the investigator
- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
- Women of childbearing potential having a negative serum pregnancy test at screening and within 48 hours before infusion of ARGX-110 on Day -14, and willing to use an effective contraceptive method (intrauterine devices, hormonal contraceptives, contraceptive pill, implants, transdermal patches, hormonal vaginal devices, infusions with prolonged release) during the study and for at least 3 months after the last study drug administration
Exclusion Criteria:
- Prior or concurrent malignancy, except for the following: (1) adequately treated basal cell or squamous cell skin cancer; (2) carcinoma in situ of the cervix; (3) carcinoma in situ of the breast; (4) incidental histological finding of Prostate cancer (Tumour, Node, Metastasis [TNM] stage T1a or T1b), or; (5) Any other cancer from which the subject has been disease-free for more than 2 years
- Any previous AML or MDS chemo- or radiotherapy (with the exception of hydroxyurea/Litalir for leukocyte control which should be discontinued by the first day of AZA, local radiation therapy, therapy for basal or squamous cell carcinoma of the skin)
- Treatment with any investigational product within 4 weeks before the first administration of ARGX-110
- Any known active or chronic infection, including human immunodeficiency virus (HIV) and hepatitis B or C virus infection
- Any other concurrent disease or medical condition that is likely to interfere with study procedures or results, or that in the opinion of the investigator would constitute a hazard for participating in this study
Sites / Locations
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
ARGX-110 with Azacytidine (AZA)
Arm Description
Phase 1: Participants will receive loading dose of ARGX-110 1 milligram per kilogram (mg/kg) body weight (cohort 1), 3 mg/kg body weight (cohort 2), 10 mg/kg body weight (cohort 3) or 20 mg/kg body weight (cohort 4) administered intravenously (IV) in combination with AZA standard dose of 75 milligram per meter square (mg/m^2) body surface area (BSA) administered subcutaneously (SC) / intravenously (IV). Phase 2: Participants will receive loading dose of ARGX-110 IV at a recommended dose for Phase 2 (RP2D) level from phase 1 in combination with AZA standard dose of 75 mg/m^2 BSA, administered SC/IV as per local practice.
Outcomes
Primary Outcome Measures
Phase 1: Number of Participants with Dose Limiting Toxicity (DLT)
DLTs will be defined as any of the following drug-related events: Any grade 3 or higher drug related non-hematological toxicity or; Grade 3 or higher IRRs or; inability to administer the next dose due to a drug-related adverse event or a delay of the administration of the next dose due to toxicities for more than 14 days despite adequate medication or; drug-related grade 4 febrile neutropenia or; drug-related grade 4 anemia which cannot be adequately treated.
Phase 2: Overall Response Rate (ORR)
ORR is defined as the sum of Complete remission (CR), CR with incomplete recovery (CRi), morphologic leukemia-free state (MLFS), partial remission (PR) at the ARGX-110 RP2D level that was established in Phase 1 according to established response criteria for Acute myeloid leukemia (AML).
Secondary Outcome Measures
Phase 1 and Phase 2: Number of Participants with Adverse Events
An AE is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product.
Phase 1 and Phase 2: Maximum Observed Concentration (Cmax) of ARGX-110
Cmax is the maximum observed concentration.
Phase 1 and Phase 2: Trough Concentration (Ctrough) of ARGX-110
Ctrough is defined as the observed serum concentration before dosing or at the end of the dosing interval.
Phase 1 and Phase 2: Area Under the Serum Concentration-Time Curve from Time Zero to Infinite (AUC[0-infinity]) of ARGX-110
AUC(0-infinity) is defined as area under the serum analyte concentration-time curve from time 0 to infinite time of ARGX-110.
Phase 1 and Phase 2: Area Under the Serum Concentration-Time Curve During the Dosing Interval (AUCtau)
AUCtau is the area under the serum concentration-time curve during the dosing interval.
Phase 1 and Phase 2: Apparent Volume of Distribution (Vd/F) of ARGX-110
Vd/F is defined as Dose/[Lambda (z)*AUC (0-infinity)].
Phase 1 and Phase 2: Total Systemic Clearance (CL) of ARGX-110
CL is the total systemic clearance of drug after intravenous (IV) administration.
Phase 1 and Phase 2: Elimination Half-Life (t1/2) of ARGX-110
t1/2 is defined as the time measured for the serum concentration to decrease by 1 half of its original concentration.
Phase 1 and Phase 2: Number of Participants with Minimal Residual Disease (MRD) to ARGX-110
Minimal residual disease assessments will be performed on bone marrow aspirates and/or whole blood by flow cytometry.
Phase 1 and Phase 2: Number of Participants with Anti-drug Antibodies (ADA) to ARGX-110
Venous blood samples and bone marrow aspirate will be used to evaluate presence of anti-drug antibodies to ARGX-110. Participants with titer of confirmed positive samples for ARGX-110 antibodies will be reported.
Phase 1 and Phase 2: Number of Participants with Complete Remission (CR)
Complete remission is defined as number of participants who have bone marrow blasts less than (<) 5 percent (%); absence of blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count greater than (>) 1.0 * 10^9 per liter (L) (1000 per microliter [µL]); platelet count > 100 * 10^9/L (100.000/mc); independence of red cell transfusions.
Phase 1 and Phase 2: Number of Participants with CR with Incomplete Recovery (CRi)
CRi is defined as number of participants who have all CR criteria except for residual neutropenia (< 1.0 * 10^9/L [1000/mc]) or thrombocytopenia (< 100 * 10^9/L [100.000/mc]).
Phase 1 and Phase 2: Number of Participants with Morphologic Leukemia-free State (MLFS)
MLFS is defined as number of participants who have bone marrow blasts < 5%; absence of blasts with Auer rods; absence of extramedullary disease; no hematologic recovery required.
Phase 1 and Phase 2: Number of Participants with Partial remission (PR)
PR is defined as number of participants who have all hematologic criteria of CR; decrease of bone marrow blast percentage to 5% to 25%; and decrease of pretreatment bone marrow blast percentage by at least 50%.
Phase 1 and Phase 2: Time to Response
Time to response is defined as response measured from the time from first dose of study drug to date of response (CR, CRi, MLFS, PR).
Phase 1 and Phase 2: Duration of Response
Duration of response is defined as the date of achievement of a response (CR, CRi, MLFS, PR) until the date of relapse.
Phase 1 and Phase 2: Relapse-Free Survival (RFS)
RFS is defined as disease relapse or participant death from any cause; measured from the date of achievement of a remission (CR, CRi) until the date of relapse or death from any cause.
Phase 1 and Phase 2: Overall Survival (OS)
OS is defined as death from any cause; measured from the date of first dose to the date of death from any cause.
Phase 1 and Phase 2: Number of Participants with 30 Day and 60 Day Mortality
Number of participants with 30 Day and 60 Day Mortality will be reported.
Phase 1 and Phase 2: Number of Participants Achieving Transfusion Independence (TI)
Number of participants reaching greater than or equal to (>=) 8 consecutive weeks without red blood cell (RBC-TI) and/or platelet (PLT-TI) transfusion. The first day of the >=8-week period with no transfusions is noted as the time at which participants first achieved TI.
Phase 1 and Phase 2: Time to Transfusion Independence
Time until TI for RBC and/or PLT will be measured from the date of entry into a study to the first day of the 8-weeks period with no transfusions.
Phase 1 and Phase 2: Duration of Transfusion Independence
Time between the last transfusion before the start of the TI period and the first transfusion after the start of the TI period, which occurred >=8 weeks later.
Phase 1 and Phase 2: Time to Neutrophil Recovery
Time to neutrophil recovery will be calculated from number of days from Day 1 of commencing study treatment to first day neutrophils 0.5 * 10^9 per liter or 1.0 * 10^9 per liter.
Phase 1 and Phase 2: Time to Platelet Recovery
Time to platelet recovery will be calculated from number of days from day 1 of commencing study treatment to first day neutrophils 50 * 10^9 per liter or 100 * 10^9 per liter.
Biomarker Assessment of ARGX-110
Biomarkers including CD70 and CD27 assessment will be performed on bone marrow aspirates and/or whole blood.
Phase 1: Levels of T, B and NK Cells
Levels of T, B and NK cells will be reported by immunophenotyping (performed by flow cytometry or mass cytometry). .
Phase 1: Levels of B Cells
Levels of B cells will be reported.
Phase 1: Levels of NK Cells
Levels of NK cells will be reported.
Full Information
NCT ID
NCT03030612
First Posted
January 23, 2017
Last Updated
August 7, 2023
Sponsor
OncoVerity, Inc.
Collaborators
argenx, Janssen Research & Development, LLC
1. Study Identification
Unique Protocol Identification Number
NCT03030612
Brief Title
A Study of ARGX-110 in Combination With Azacytidine in Participants With Newly Diagnosed Acute Myeloid Leukemia (AML) or High Risk Myelodysplatic Syndrome (MDS)
Official Title
A Phase I/II, Open-label, Dose-Escalating Study With a Proof of Concept Cohort to Evaluate the Safety, Tolerability and Efficacy of ARGX-110 in Combination With Azacytidine in Subjects With Newly Diagnosed Acute Myeloid Leukemia (AML) or High Risk Myelodysplatic Syndrome (MDS)
Study Type
Interventional
2. Study Status
Record Verification Date
August 2023
Overall Recruitment Status
Completed
Study Start Date
December 2016 (Actual)
Primary Completion Date
August 2022 (Actual)
Study Completion Date
August 2022 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
OncoVerity, Inc.
Collaborators
argenx, Janssen Research & Development, LLC
4. Oversight
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The purpose of this study is to determine the maximum tolerated dose (MTD) of ARGX-110 and/or the recommended Phase II dose (RP2D) in combination with a standard dose of azacytidine (AZA) in Phase 1; and to evaluate efficacy of ARGX-110 when administered at a RP2D level established in Phase I in combination with a standard dose of AZA (proof-of concept) by evaluating overall response rate (ORR) in Phase 2.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Leukemia, Myeloid, Acute, Myelodysplastic Syndromes
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
38 (Actual)
8. Arms, Groups, and Interventions
Arm Title
ARGX-110 with Azacytidine (AZA)
Arm Type
Experimental
Arm Description
Phase 1: Participants will receive loading dose of ARGX-110 1 milligram per kilogram (mg/kg) body weight (cohort 1), 3 mg/kg body weight (cohort 2), 10 mg/kg body weight (cohort 3) or 20 mg/kg body weight (cohort 4) administered intravenously (IV) in combination with AZA standard dose of 75 milligram per meter square (mg/m^2) body surface area (BSA) administered subcutaneously (SC) / intravenously (IV). Phase 2: Participants will receive loading dose of ARGX-110 IV at a recommended dose for Phase 2 (RP2D) level from phase 1 in combination with AZA standard dose of 75 mg/m^2 BSA, administered SC/IV as per local practice.
Intervention Type
Drug
Intervention Name(s)
ARGX-110
Other Intervention Name(s)
Cusatuzumab, JNJ-74494550
Intervention Description
ARGX-110 will be administered intravenously.
Intervention Type
Drug
Intervention Name(s)
AZA
Intervention Description
AZA will be administered subcutaneously/intravenously.
Primary Outcome Measure Information:
Title
Phase 1: Number of Participants with Dose Limiting Toxicity (DLT)
Description
DLTs will be defined as any of the following drug-related events: Any grade 3 or higher drug related non-hematological toxicity or; Grade 3 or higher IRRs or; inability to administer the next dose due to a drug-related adverse event or a delay of the administration of the next dose due to toxicities for more than 14 days despite adequate medication or; drug-related grade 4 febrile neutropenia or; drug-related grade 4 anemia which cannot be adequately treated.
Time Frame
Up to 3.6 years
Title
Phase 2: Overall Response Rate (ORR)
Description
ORR is defined as the sum of Complete remission (CR), CR with incomplete recovery (CRi), morphologic leukemia-free state (MLFS), partial remission (PR) at the ARGX-110 RP2D level that was established in Phase 1 according to established response criteria for Acute myeloid leukemia (AML).
Time Frame
Up to 3.6 years
Secondary Outcome Measure Information:
Title
Phase 1 and Phase 2: Number of Participants with Adverse Events
Description
An AE is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product.
Time Frame
Up to 3.6 years
Title
Phase 1 and Phase 2: Maximum Observed Concentration (Cmax) of ARGX-110
Description
Cmax is the maximum observed concentration.
Time Frame
Up to 3.6 years
Title
Phase 1 and Phase 2: Trough Concentration (Ctrough) of ARGX-110
Description
Ctrough is defined as the observed serum concentration before dosing or at the end of the dosing interval.
Time Frame
Up to 3.6 years
Title
Phase 1 and Phase 2: Area Under the Serum Concentration-Time Curve from Time Zero to Infinite (AUC[0-infinity]) of ARGX-110
Description
AUC(0-infinity) is defined as area under the serum analyte concentration-time curve from time 0 to infinite time of ARGX-110.
Time Frame
Up to 3.6 years
Title
Phase 1 and Phase 2: Area Under the Serum Concentration-Time Curve During the Dosing Interval (AUCtau)
Description
AUCtau is the area under the serum concentration-time curve during the dosing interval.
Time Frame
Up to 3.6 years
Title
Phase 1 and Phase 2: Apparent Volume of Distribution (Vd/F) of ARGX-110
Description
Vd/F is defined as Dose/[Lambda (z)*AUC (0-infinity)].
Time Frame
Up to 3.6 years
Title
Phase 1 and Phase 2: Total Systemic Clearance (CL) of ARGX-110
Description
CL is the total systemic clearance of drug after intravenous (IV) administration.
Time Frame
Up to 3.6 years
Title
Phase 1 and Phase 2: Elimination Half-Life (t1/2) of ARGX-110
Description
t1/2 is defined as the time measured for the serum concentration to decrease by 1 half of its original concentration.
Time Frame
Up to 3.6 years
Title
Phase 1 and Phase 2: Number of Participants with Minimal Residual Disease (MRD) to ARGX-110
Description
Minimal residual disease assessments will be performed on bone marrow aspirates and/or whole blood by flow cytometry.
Time Frame
Up to 3.6 years
Title
Phase 1 and Phase 2: Number of Participants with Anti-drug Antibodies (ADA) to ARGX-110
Description
Venous blood samples and bone marrow aspirate will be used to evaluate presence of anti-drug antibodies to ARGX-110. Participants with titer of confirmed positive samples for ARGX-110 antibodies will be reported.
Time Frame
Up to 3.6 years
Title
Phase 1 and Phase 2: Number of Participants with Complete Remission (CR)
Description
Complete remission is defined as number of participants who have bone marrow blasts less than (<) 5 percent (%); absence of blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count greater than (>) 1.0 * 10^9 per liter (L) (1000 per microliter [µL]); platelet count > 100 * 10^9/L (100.000/mc); independence of red cell transfusions.
Time Frame
Up to 3.6 years
Title
Phase 1 and Phase 2: Number of Participants with CR with Incomplete Recovery (CRi)
Description
CRi is defined as number of participants who have all CR criteria except for residual neutropenia (< 1.0 * 10^9/L [1000/mc]) or thrombocytopenia (< 100 * 10^9/L [100.000/mc]).
Time Frame
Up to 3.6 years
Title
Phase 1 and Phase 2: Number of Participants with Morphologic Leukemia-free State (MLFS)
Description
MLFS is defined as number of participants who have bone marrow blasts < 5%; absence of blasts with Auer rods; absence of extramedullary disease; no hematologic recovery required.
Time Frame
Up to 3.6 years
Title
Phase 1 and Phase 2: Number of Participants with Partial remission (PR)
Description
PR is defined as number of participants who have all hematologic criteria of CR; decrease of bone marrow blast percentage to 5% to 25%; and decrease of pretreatment bone marrow blast percentage by at least 50%.
Time Frame
Up to 3.6 years
Title
Phase 1 and Phase 2: Time to Response
Description
Time to response is defined as response measured from the time from first dose of study drug to date of response (CR, CRi, MLFS, PR).
Time Frame
Up to 3.6 years
Title
Phase 1 and Phase 2: Duration of Response
Description
Duration of response is defined as the date of achievement of a response (CR, CRi, MLFS, PR) until the date of relapse.
Time Frame
Up to 3.6 years
Title
Phase 1 and Phase 2: Relapse-Free Survival (RFS)
Description
RFS is defined as disease relapse or participant death from any cause; measured from the date of achievement of a remission (CR, CRi) until the date of relapse or death from any cause.
Time Frame
Up to 3.6 years
Title
Phase 1 and Phase 2: Overall Survival (OS)
Description
OS is defined as death from any cause; measured from the date of first dose to the date of death from any cause.
Time Frame
Up to 3.6 years
Title
Phase 1 and Phase 2: Number of Participants with 30 Day and 60 Day Mortality
Description
Number of participants with 30 Day and 60 Day Mortality will be reported.
Time Frame
30 and/or 60 days after the first administration
Title
Phase 1 and Phase 2: Number of Participants Achieving Transfusion Independence (TI)
Description
Number of participants reaching greater than or equal to (>=) 8 consecutive weeks without red blood cell (RBC-TI) and/or platelet (PLT-TI) transfusion. The first day of the >=8-week period with no transfusions is noted as the time at which participants first achieved TI.
Time Frame
Up to 3.6 years
Title
Phase 1 and Phase 2: Time to Transfusion Independence
Description
Time until TI for RBC and/or PLT will be measured from the date of entry into a study to the first day of the 8-weeks period with no transfusions.
Time Frame
Up to 3.6 years
Title
Phase 1 and Phase 2: Duration of Transfusion Independence
Description
Time between the last transfusion before the start of the TI period and the first transfusion after the start of the TI period, which occurred >=8 weeks later.
Time Frame
Up to 3.6 years
Title
Phase 1 and Phase 2: Time to Neutrophil Recovery
Description
Time to neutrophil recovery will be calculated from number of days from Day 1 of commencing study treatment to first day neutrophils 0.5 * 10^9 per liter or 1.0 * 10^9 per liter.
Time Frame
Up to 3.6 years
Title
Phase 1 and Phase 2: Time to Platelet Recovery
Description
Time to platelet recovery will be calculated from number of days from day 1 of commencing study treatment to first day neutrophils 50 * 10^9 per liter or 100 * 10^9 per liter.
Time Frame
Up to 3.6 years
Title
Biomarker Assessment of ARGX-110
Description
Biomarkers including CD70 and CD27 assessment will be performed on bone marrow aspirates and/or whole blood.
Time Frame
Up to 3.6 years
Title
Phase 1: Levels of T, B and NK Cells
Description
Levels of T, B and NK cells will be reported by immunophenotyping (performed by flow cytometry or mass cytometry). .
Time Frame
Up to 3.6 years
Title
Phase 1: Levels of B Cells
Description
Levels of B cells will be reported.
Time Frame
Up to 3.6 years
Title
Phase 1: Levels of NK Cells
Description
Levels of NK cells will be reported.
Time Frame
Up to 3.6 years
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Signed informed consent form (ICF) indicating an understanding of the purposes, risks, and procedures required for the study and willingness and ability to participate in the study
Acute myeloid leukemia (AML) or high risk myelodysplastic syndrome (MDS) (according to 2016 World Health Organization [WHO] classification definition of greater than or equal to [>=] 20 percent [%] blasts) (bone marrow) unsuitable for intensive treatment (including stem cell transplantation) with a curative intent, but eligible to receive azacytidine (AZA) treatment
Expected life expectancy >= 3 months, at the discretion of the investigator
Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
Women of childbearing potential having a negative serum pregnancy test at screening and within 48 hours before infusion of ARGX-110 on Day -14, and willing to use an effective contraceptive method (intrauterine devices, hormonal contraceptives, contraceptive pill, implants, transdermal patches, hormonal vaginal devices, infusions with prolonged release) during the study and for at least 3 months after the last study drug administration
Exclusion Criteria:
Prior or concurrent malignancy, except for the following: (1) adequately treated basal cell or squamous cell skin cancer; (2) carcinoma in situ of the cervix; (3) carcinoma in situ of the breast; (4) incidental histological finding of Prostate cancer (Tumour, Node, Metastasis [TNM] stage T1a or T1b), or; (5) Any other cancer from which the subject has been disease-free for more than 2 years
Any previous AML or MDS chemo- or radiotherapy (with the exception of hydroxyurea/Litalir for leukocyte control which should be discontinued by the first day of AZA, local radiation therapy, therapy for basal or squamous cell carcinoma of the skin)
Treatment with any investigational product within 4 weeks before the first administration of ARGX-110
Any known active or chronic infection, including human immunodeficiency virus (HIV) and hepatitis B or C virus infection
Any other concurrent disease or medical condition that is likely to interfere with study procedures or results, or that in the opinion of the investigator would constitute a hazard for participating in this study
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Janssen Research & Development, LLC Clinical Trial
Organizational Affiliation
Janssen Research & Development, LLC
Official's Role
Study Director
Facility Information:
City
Marseille Cedex 9
Country
France
City
Paris Cedex 10
Country
France
City
Pierre - Bénite Cedex
Country
France
City
Toulouse Cedex 9
Country
France
City
Aarau
Country
Switzerland
City
Bern
Country
Switzerland
City
Zürich
Country
Switzerland
12. IPD Sharing Statement
Plan to Share IPD
Undecided
Citations:
PubMed Identifier
32601337
Citation
Riether C, Pabst T, Hopner S, Bacher U, Hinterbrandner M, Banz Y, Muller R, Manz MG, Gharib WH, Francisco D, Bruggmann R, van Rompaey L, Moshir M, Delahaye T, Gandini D, Erzeel E, Hultberg A, Fung S, de Haard H, Leupin N, Ochsenbein AF. Targeting CD70 with cusatuzumab eliminates acute myeloid leukemia stem cells in patients treated with hypomethylating agents. Nat Med. 2020 Sep;26(9):1459-1467. doi: 10.1038/s41591-020-0910-8. Epub 2020 Jun 29.
Results Reference
derived
Learn more about this trial
A Study of ARGX-110 in Combination With Azacytidine in Participants With Newly Diagnosed Acute Myeloid Leukemia (AML) or High Risk Myelodysplatic Syndrome (MDS)
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