A Study of ARGX-110 in Combination With Azacytidine in Participants With Newly Diagnosed Acute Myeloid Leukemia (AML) or High Risk Myelodysplatic Syndrome (MDS)

Myelodysplastic Syndromes Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03030612
• Other study ID #: CR108756
• Secondary ID: 2016-002151-17AR
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: December 2016
• Est. completion date: August 2022

Study information

• Verified date: August 2023
• Source: OncoVerity, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 38
• Est. completion date: August 2022
• Est. primary completion date: August 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Myelodysplastic Syndromes
• Syndrome

Intervention

Drug:
• ARGX-110
ARGX-110 will be administered intravenously.
• AZA
AZA will be administered subcutaneously/intravenously.

Locations

Country	Name	City	State
n/a

Sponsors (3)

Lead Sponsor	Collaborator
OncoVerity, Inc.	argenx, Janssen Research & Development, LLC

Countries where clinical trial is conducted

France,  Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	Up to 3.6 years
Primary	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).	Up to 3.6 years
Secondary	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.	Up to 3.6 years
Secondary	Phase 1 and Phase 2: Maximum Observed Concentration (Cmax) of ARGX-110	Cmax is the maximum observed concentration.	Up to 3.6 years
Secondary	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.	Up to 3.6 years
Secondary	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.	Up to 3.6 years
Secondary	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.	Up to 3.6 years
Secondary	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)].	Up to 3.6 years
Secondary	Phase 1 and Phase 2: Total Systemic Clearance (CL) of ARGX-110	CL is the total systemic clearance of drug after intravenous (IV) administration.	Up to 3.6 years
Secondary	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.	Up to 3.6 years
Secondary	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.	Up to 3.6 years
Secondary	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.	Up to 3.6 years
Secondary	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.	Up to 3.6 years
Secondary	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]).	Up to 3.6 years
Secondary	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.	Up to 3.6 years
Secondary	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%.	Up to 3.6 years
Secondary	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).	Up to 3.6 years
Secondary	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.	Up to 3.6 years
Secondary	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.	Up to 3.6 years
Secondary	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.	Up to 3.6 years
Secondary	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.	30 and/or 60 days after the first administration
Secondary	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.	Up to 3.6 years
Secondary	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.	Up to 3.6 years
Secondary	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.	Up to 3.6 years
Secondary	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.	Up to 3.6 years
Secondary	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.	Up to 3.6 years
Secondary	Biomarker Assessment of ARGX-110	Biomarkers including CD70 and CD27 assessment will be performed on bone marrow aspirates and/or whole blood.	Up to 3.6 years
Secondary	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). .	Up to 3.6 years
Secondary	Phase 1: Levels of B Cells	Levels of B cells will be reported.	Up to 3.6 years
Secondary	Phase 1: Levels of NK Cells	Levels of NK cells will be reported.	Up to 3.6 years