A Study of Cusatuzumab in Combination With Azacitidine Compared With Azacitidine Alone in Patients With Higher-risk Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML) and Who Are Not Candidates for Hematopoietic Stem Cell Transplantation (HSCT)

A Phase 2, Randomized, Open-label Study of Cusatuzumab in Combination With Azacitidine Compared With Azacitidine Alone in Patients With Higher-risk Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML) and Who Are Not Candidates for Hematopoietic Stem Cell Transplantation (HSCT)

The purpose of the study is to compare overall response rate (ORR) between treatment groups in participants with higher-risk Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML) who are not eligible for Hematopoietic Stem Cell Transplantation (HSCT).

Study Overview

• Status: Withdrawn
• Conditions: Myelodysplastic Syndromes; Leukemia, Myelomonocytic, Chronic
• Intervention / Treatment: Drug: Azacitidine; Drug: Cusatuzumab

Detailed Description

Cusatuzumab (also known as JNJ-74494550 and ARGX-110) is a humanized monoclonal antibody of camelid origin that binds with high affinity to human Cluster of Differentiation 70 (CD70). Azacitidine (an Hypomethylating agent [HMA]) is approved for the treatment of higher-risk MDS in the United States (US) and the European Union (EU). Both approvals are based on data showing decreased transfusion burden, delayed progression to acute myeloid leukemia (AML), improved quality of life, and extended survival. It is hypothesized that the addition of cusatuzumab to azacitidine will result in an improvement in overall response rate (ORR) compared with azacitidine alone in participants with higher-risk MDS or CMML.

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Darlinghurst, Australia, 2010
    • St Vincents Hospital Sydney
  • Fitzroy, Australia, 3065
    • St Vincents Hospital Melbourne
  • Melbourne, Australia
    • Peter MacCallum Cancer Institute
  • Perth, Australia, 6000
    • Royal Perth Hospital
  • Westmead, Australia, 2145
    • Westmead Hospital
  • Wollongong, Australia, 2500
    • Wollongong Hospital
• Brazil
  • Curitiba, Brazil, 81520-060
    • Hospital Erasto Gaertner- Liga Paranaense de Combate ao Câncer
  • Florianopolis, Brazil, 88034-000
    • CEPON - Centro de Pesquisas Oncológicas
  • Natal, Brazil, 59062-000
    • Liga Norte Riograndense Contra o Câncer
  • Porto Alegre, Brazil, 90035-903
    • Hospital de Clinicas de Porto Alegre
  • Porto Alegre, Brazil, 90110-270
    • Instituto do cancer -COR -Hospital Mae de Deus
  • Rio De Janeiro, Brazil, 22250-905
    • Oncoclínicas
  • São José do Rio Preto, Brazil, 15090-000
    • Hospital de Base de Sao Jose do Rio Preto
  • São Paulo, Brazil, 01321-001
    • Hospital Paulistano
  • São Paulo, Brazil, 4501000
    • Instituto D'Or de Pesquisa e Ensino (IDOR)
• France
  • Angers, France, 49933
    • CHU d'Angers
  • Lille, France, 59020
    • Hôpital Saint Vincent de Paul
  • Limoges, France, 87042
    • CHU de Limoges, Hopital Dupuytren
  • Marseille, France, 13005
    • Hôpital de la Conception
  • Nice, France, 06200
    • CHU de Nice Hopital de l Archet
  • Paris Cedex 10, France, 75475
    • Hôpital Saint-Louis
  • Paris, 75, France, 75674
    • Hôpital Cochin APHP
  • Tours, France, 37000
    • CHRU Tours Hopital Bretonneau
  • Vandoeuvre Les Nancy, France, 54500
    • CHU de Nancy_ Hopital Brabois
• Germany
  • Dresden, Germany, 01307
    • Universitatsklinikum Carl Gustav Carcus Dresden
  • Freiburg Im Breisgau, Germany, 79106
    • Universitätsklinik Freiburg
  • Hannover, Germany, 30625
    • Medizinische Hochschule Hannover
  • Leipzig, Germany, 04103
    • Universitatsklinikum Leipzig
  • München, Germany, 81675
    • Klinikum rechts der Isar an der Technischen Universitat Munchen
  • Ulm, Germany, 89081
    • Universitaetsklinikum Ulm
• Italy
  • Bologna, Italy, 40138
    • Policlinico Sant'Orsola Malpighi
  • Cona, Italy, 44124
    • Azienda Ospedaliero Universitaria di Ferrara
  • Novara, Italy, 28100
    • Università del Piemonte Orientale - Ospedale Maggiore della Carità di Novara
  • Orbassano, Italy, 10043
    • AOU San Luigi Gonzaga
  • Reggio Calabria, Italy, 89124
    • Grande Ospedale Metropolitano 'Bianchi-Melacrino-Morelli' Reggio Calabria
  • Roma, Italy, 00161
    • Policlinico Umberto I
  • Roma, Italy, 00133
    • Fondazione Policlinico Tor Vergata
  • Rozzano, Italy, 20089
    • Istituto Clinico Humanitas
• Russian Federation
  • Dzerzhinsk, Russian Federation, 606019
    • Emergency Hospital of Dzerzhinsk
  • Moscow, Russian Federation, 125284
    • S.P. Botkin Moscow City Clinical Hospital
  • Nizhny Novgorod, Russian Federation, 603126
    • Nizhniy Novgorod Region Clinical Hospital
  • Ryazan, Russian Federation, 390039
    • Ryazan Regional Clinical Hospital
  • Saint-Petersburg, Russian Federation, 123182
    • Saint Petersburg City Hospital #15
  • St-Petersburg, Russian Federation, 191024
    • Clinical Research Institute of Hematology and Transfusiology
  • St. Petersburg, Russian Federation, 197110
    • St.-Petersburg City Clinical Hospital nr 31
  • Syktyvkar, Russian Federation, 167904
    • Oncology Dispensary of Komi Republic
• Saudi Arabia
  • Dammam, Saudi Arabia, 15215
    • King Fahad Specialist Hospital
  • Jeddah, Saudi Arabia, 21423
    • King Abdulaziz Medical City
  • Riyadh, Saudi Arabia, 12713
    • King Faisal Specialist Hospital & Research Center
• Spain
  • Badalona, Spain, 08916
    • Hosp. Univ. Germans Trias I Pujol
  • Barcelona, Spain, 08041
    • Hosp. de La Santa Creu I Sant Pau
  • Barcelona, Spain, 08035
    • Hosp. Univ. Vall D Hebron
  • Barcelona, Spain, 08908
    • Inst. Cat. Doncologia-H Duran I Reynals
  • Madrid, Spain, 28031
    • Hosp. Univ. Infanta Leonor
  • Madrid, Spain, 28050
    • Centro Integral Oncológico Clara Campal
  • Palma, Spain, 7120
    • Hosp. Univ. Son Espases
  • Salamanca, Spain, 37007
    • Hosp. Clinico Univ. de Salamanca
  • Sevilla, Spain, 41013
    • Hosp. Virgen Del Rocio
• Switzerland
  • Bern, Switzerland, 3010
    • Inselspital, Universitätsspital Bern
  • Geneve, Switzerland, 1205
    • Hôpitaux Universitaires de Genève
  • Zürich, Switzerland
    • Universitaetsspital Zuerich
• Turkey
  • Ankara, Turkey, 06010
    • Gulhane Egitim ve Arastirma Hastanesi
  • Ankara, Turkey, 06200
    • Dr.Abdurrahman Yurtaslan Oncology Training and Research Hospital
  • Ankara, Turkey, 06590
    • Ankara Universitesi Tip Fakultesi
  • Istanbul, Turkey, 34010
    • Koç Üniversitesi Hastanesi
  • Izmir, Turkey, 35100
    • Ege Universitesi Tip Fakultesi
  • Izmir, Turkey, 35340
    • Dokuz Eylul Universitesi Tip Fakultesi
  • Samsun, Turkey, 55200
    • Ondokuz Mayis Universitesi Tip Fakultesi
• United Kingdom
  • Leeds, United Kingdom, LS9 7TF
    • St James Hospital
  • London, United Kingdom, NW1 2BU
    • University College London Hospitals
  • London, United Kingdom, SE5 9RF
    • Kings College Hospital
  • Newcastle Upun Tyne, United Kingdom, NE1 4LP
    • Royal Victoria Infirmary
  • Oxford, United Kingdom, OX3 7LE
    • Churchill Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of de novo or secondary higher-risk Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML) per World Health Organization (WHO) 2016 criteria
• At study entry, higher-risk MDS (intermediate, high, and very high risk MDS per Revised International Prognostic Scoring System [IPSS R]) OR higher-risk CMML (intermediate-2 or high risk CMML per CMML-specific Prognostic Scoring System [CPSS-Mol]). Participants with previous lower-risk MDS or CMML that has evolved to higher-risk MDS or CMML are eligible
• At study entry, not a candidate for Hematopoietic Stem Cell Transplantation (HSCT)
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2
• Adequate liver and renal function defined as follows: Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) less than (<) 3 * upper limit of normal (ULN); Total bilirubin less than or equal to (<=) 1.5 * ULN, unless bilirubin rise is due to Gilbert's syndrome or of non hepatic origin; and Creatinine clearance (CrCl) greater than (>) 30 milliliter per minute per 1.73 square meters (mL/min/1.73 m^2) (by Modification of Diet in Renal Disease formula)

Exclusion Criteria:

• Received prior HSCT or any prior treatment, including hypomethylating agent (HMAs), for higher-risk MDS or CMML. Prior supportive therapies including transfusion and growth factors are acceptable
• Received prior treatment with cusatuzumab
• Presence of the breakpoint cluster region protein-Abelson murine leukemia (bcr-abl) rearrangement
• Received a live, attenuated vaccine within 4 weeks prior to initiation of study drug
• Any active systemic infection

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Azacitidine: Participants with MDS or CMML; Participants with higher-risk Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML) will receive azacitidine 75 milligram per meter square (mg/m^2) body surface area (BSA) subcutaneously or Intravenously per local label on Days 1 through Day 7 of each 28-day cycle. Participants will be treated until disease progression; relapse from complete remission (CR), partial remission (PR), or marrow complete remission (mCR); transformation to acute myeloid leukemia (AML); death; or unacceptable toxicity.	Drug: Azacitidine; Participants will receive subcutaneous (SC) or intravenous (IV) injection of Azacitidine 75 mg/m^2.
Experimental: Azacitidine and Cusatuzumab: Participants with MDS or CMML; Participants with higher-risk MDS or CMML will receive azacitidine 75 mg/m^2 BSA subcutaneously or Intravenously per local label on Days 1 through 7 and cusatuzumab 20 mg/kg IV on Days 3 and 17 of each 28-day cycle. Participants will be treated until disease progression; relapse from CR, PR, mCR; transformation to AML; death; or unacceptable toxicity.	Drug: Azacitidine; Participants will receive subcutaneous (SC) or intravenous (IV) injection of Azacitidine 75 mg/m^2.; Drug: Cusatuzumab; Participants will receive SC or IV injection of Cusatuzumab 20 mg/kg.; Other Names: JNJ-74494550,; ARGX-110

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR)	ORR is a composite of complete remission (CR), partial remission (PR) and marrow complete remission (mCR) as per modified International Working Group (IWG) criteria.	Up to 4 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Achieving Complete Remission (CR)	Percentage of participants achieving CR as per IWG criteria will be reported.	Up to 4 years
Percentage of Participants who Achieve Transfusion Independence	Percentage of participants who achieve transfusion independence will be reported. Transfusion independence is defined as a period of greater than or equal to (>=) 56 consecutive days with no transfusion occurring between the first and last dose of study drug +30 days.	Up to 4 years
Time to Transformation of Participants to Acute Myeloid Leukemia (AML)	Time to transformation of participants to AML will be reported. Transformation to AML is defined as >= 20% bone marrow blasts.	Up to 4 years
Progression Free Survival (PFS)	PFS is defined as the time from randomization to disease progression; relapse from CR, PR, or mCR; or death from any cause.	Up to 4 years
Overall Survival (OS)	OS is defined as the time from randomization to death.	Up to 4 years
Hematologic Improvement Rate	Hematologic improvement rate is defined as erythroid response (pretreatment, less than (<) 11 g/dL; hemoglobin >= 1.5 g/dL; relevant reduction of units of RBC transfusions by an absolute number of >= 4 Red blood cell (RBC) transfusions/8 weeks compared with the pretreatment transfusion number in the previous 8 weeks. Only RBC transfusions given for a hemoglobin of <= 9.0 g/dL pretreatment will count in the RBC transfusion response evaluation; platelet response (pretreatment <100*10^9/L); absolute increase of >= 30*109/L for participants starting with >20*10^9/L platelets; increase to >20*109/L and by >= 100% for participants starting with <= 20*109/L platelets; Neutrophil response (pretreatment <1.0×10^9/L); and at least 100% increase and an absolute increase of >0.5*10^9/L.	Up to 4 years
Percentage of Participants With Adverse Events (AEs) as a Measure of Safety and Tolerability	An adverse event 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 4 years
Percentage of Participants With Clinically Significant Abnormalities in Laboratory Parameters	Percentage of participants with clinically significant abnormalities in laboratory parameters will be reported.	Up to 4 years
Area Under the Serum Concentration-Time Curve Within Timespan t1 to t2 (AUC[t1-t2]) of Cusatuzumab	The AUC(t1-t2) is the area under the serum concentration-time curve within timespan t1 to t2.	Cycle 1: Day 3,17 (predose, end of infusion [EOI] postdose), Day 4 (24 hours postdose) Cycle 2, 3, 4, 8, 11: Day 3 (predose, EOI postdose); Cycle 4 Day 21 to Cycle 5: Day 1(at disease evaluation); and end of treatment (EOT) [up to 4 years])
Maximum Serum Concentration (Cmax) of Cusatuzumab	Cmax is the maximum observed serum concentration.	Cycle 1: Day 3,17 (predose, end of infusion [EOI] postdose), Day 4 (24 hours postdose) Cycle 2, 3, 4, 8, 11: Day 3 (predose, EOI postdose); Cycle 4 Day 21 to Cycle 5: Day 1(at disease evaluation); and end of treatment (EOT) [up to 4 years])
Minimum Serum Concentration (Cmin) of Cusatuzumab	Cmin is the minimum observed serum concentration.	Cycle 1: Day 3,17 (predose, end of infusion [EOI] postdose), Day 4 (24 hours postdose) Cycle 2, 3, 4, 8, 11: Day 3 (predose, EOI postdose); Cycle 4 Day 21 to Cycle 5: Day 1(at disease evaluation); and end of treatment (EOT) [up to 4 years])
Elimination Half-Life (t1/2) of Cusatuzumab	T1/2 is the time measured for the serum concentration to decrease by 1 half to its original concentration. It is associated with the terminal slope of the semi logarithmic drug concentration-time curve, and is calculated as 0.693/lambda(z).	Cycle 1: Day 3,17 (predose, end of infusion [EOI] postdose), Day 4 (24 hours postdose) Cycle 2, 3, 4, 8, 11: Day 3 (predose, EOI postdose); Cycle 4 Day 21 to Cycle 5: Day 1(at disease evaluation); and end of treatment (EOT) [up to 4 years])
Systemic Clearance (CL) of Cusatuzumab	CL is a quantitative measure of the rate at which a drug substance is removed from the body.	Cycle 1: Day 3,17 (predose, end of infusion [EOI] postdose), Day 4 (24 hours postdose) Cycle 2, 3, 4, 8, 11: Day 3 (predose, EOI postdose); Cycle 4 Day 21 to Cycle 5: Day 1(at disease evaluation); and end of treatment (EOT) [up to 4 years])
Volume of Distribution (Vz) of Cusatuzumab	The Vz is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug.	Cycle 1: Day 3,17 (predose, end of infusion [EOI] postdose), Day 4 (24 hours postdose) Cycle 2, 3, 4, 8, 11: Day 3 (predose, EOI postdose); Cycle 4 Day 21 to Cycle 5: Day 1(at disease evaluation); and end of treatment (EOT) [up to 4 years])
Number of Participants with Developed Antidrug Antibodies to Cusatuzumab	Venous blood samples are analyzed for presence of antidrug antibodies to cusatuzumab. Participants with titer of confirmed positive samples for cusatuzumab antibodies are reported.	Cycle 1: Day 3 (Predose); Cycle 1: Day 17 (Predose); Cycle 2: Day 3 (Predose); Cycle 8 and 11: Day 3 (Predose) and EOT (up to 4 years)
Percentage of Participants Achieving Complete Remission (CR) and Partial Remission (PR)	Percentage of participants achieving CR and PR as per IWG criteria will be reported.	Up to 4 years
Time to response	Time to response for participants who achieved CR, PR and mCR responses, defined as time from randomization to achieving the first response of CR, PR, or mCR as per modified IWG criteria.	Up to 4 years
Duration of response	Time from achieving the first response of CR, PR, or mCR to relapse or death from any cause for those participants who responded.	Up to 4 years
Percentage of Participants With Clinically Meaningful Improvement in Functional Assessment of Cancer Therapy - Anemia Trial Outcome Index (FACT-An TOI) Total Score	FACT-An is a scale in Functional Assessment of Chronic Illness Therapy Measurement System. It consists of Functional Assessment of Cancer Therapy (general version; FACT-G) and 20 questions labeled "additional concerns" that measure anemia/fatigue. FACT-G is 27-item compilation of general questions divided into 4 primary quality of life domains: physical well-being, social/family well-being, emotional wellbeing, and functional well-being. Participants will be asked to rate scale items as it applies to past 7 days, on 5-point scale (0=Not at all, 1=A little bit, 2=Somewhat, 3=Quite a bit, 4=Very much). Negatively stated items will be reversed by subtracting the response from 4. After reversing the proper items, items are summed to a total to generate a score on (sub)scale. A summary Trial Outcome Index total score (FACT An TOI) will be calculated by summing physical well being, functional well being, and anemia symptoms subscales and higher is the score better is the quality of life.	Up to 4 years

Collaborators and Investigators

• Sponsor: Janssen Research & Development, LLC
• Collaborators: argenx

Study record dates

Study Major Dates

• Study Start (Anticipated): May 6, 2021
• Primary Completion (Anticipated): April 19, 2022
• Study Completion (Anticipated): January 28, 2025

Study Registration Dates

• First Submitted: February 7, 2020
• First Submitted That Met QC Criteria: February 7, 2020
• First Posted (Actual): February 11, 2020

Study Record Updates

• Last Update Posted (Actual): May 20, 2022
• Last Update Submitted That Met QC Criteria: May 19, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Myelodysplastic-Myeloproliferative Diseases; Leukemia, Myeloid; Syndrome; Myelodysplastic Syndromes; Leukemia; Preleukemia; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Azacitidine
• Other Study ID Numbers: CR108734; 2019-003576-40 (EudraCT Number); 74494550MDS2001 (Other Identifier: Janssen Research & Development, LLC)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: The data sharing policy of the Janssen Pharmaceutical Companies of Johnson & Johnson is available at www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at yoda.yale.edu

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No