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)

Sponsor

Janssen Research & Development, LLC (Industry)

Overall Status

Withdrawn

CT.gov ID

NCT04264806

Collaborator

argenx (Industry)

Enrollment

Locations

Arms

44.8

Anticipated Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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).

Condition or Disease	Intervention/Treatment	Phase
Myelodysplastic Syndromes Leukemia, Myelomonocytic, Chronic	Drug: Azacitidine Drug: Cusatuzumab	Phase 2

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 Design

Study Type:

Interventional

Actual Enrollment :

0 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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)

Anticipated Study Start Date :

May 6, 2021

Anticipated Primary Completion Date :

Apr 19, 2022

Anticipated Study Completion Date :

Jan 28, 2025

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

Percentage of Participants Achieving Complete Remission (CR) [Up to 4 years]
Percentage of participants achieving CR as per IWG criteria will be reported.
Percentage of Participants who Achieve Transfusion Independence [Up to 4 years]
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.
Time to Transformation of Participants to Acute Myeloid Leukemia (AML) [Up to 4 years]
Time to transformation of participants to AML will be reported. Transformation to AML is defined as >= 20% bone marrow blasts.
Progression Free Survival (PFS) [Up to 4 years]
PFS is defined as the time from randomization to disease progression; relapse from CR, PR, or mCR; or death from any cause.
Overall Survival (OS) [Up to 4 years]
OS is defined as the time from randomization to death.
Hematologic Improvement Rate [Up to 4 years]
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.
Percentage of Participants With Adverse Events (AEs) as a Measure of Safety and Tolerability [Up to 4 years]
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.
Percentage of Participants With Clinically Significant Abnormalities in Laboratory Parameters [Up to 4 years]
Percentage of participants with clinically significant abnormalities in laboratory parameters will be reported.
Area Under the Serum Concentration-Time Curve Within Timespan t1 to t2 (AUC[t1-t2]) of Cusatuzumab [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])]
The AUC(t1-t2) is the area under the serum concentration-time curve within timespan t1 to t2.
Maximum Serum Concentration (Cmax) of Cusatuzumab [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])]
Cmax is the maximum observed serum concentration.
Minimum Serum Concentration (Cmin) of Cusatuzumab [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])]
Cmin is the minimum observed serum concentration.
Elimination Half-Life (t1/2) of Cusatuzumab [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])]
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).
Systemic Clearance (CL) of Cusatuzumab [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])]
CL is a quantitative measure of the rate at which a drug substance is removed from the body.
Volume of Distribution (Vz) of Cusatuzumab [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])]
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.
Number of Participants with Developed Antidrug Antibodies to Cusatuzumab [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)]
Venous blood samples are analyzed for presence of antidrug antibodies to cusatuzumab. Participants with titer of confirmed positive samples for cusatuzumab antibodies are reported.
Percentage of Participants Achieving Complete Remission (CR) and Partial Remission (PR) [Up to 4 years]
Percentage of participants achieving CR and PR as per IWG criteria will be reported.
Time to response [Up to 4 years]
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.
Duration of response [Up to 4 years]
Time from achieving the first response of CR, PR, or mCR to relapse or death from any cause for those participants who responded.
Percentage of Participants With Clinically Meaningful Improvement in Functional Assessment of Cancer Therapy - Anemia Trial Outcome Index (FACT-An TOI) Total Score [Up to 4 years]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	St Vincents Hospital Sydney	Darlinghurst	Australia	2010
2	St Vincents Hospital Melbourne	Fitzroy	Australia	3065
3	Peter MacCallum Cancer Institute	Melbourne	Australia
4	Royal Perth Hospital	Perth	Australia	6000
5	Westmead Hospital	Westmead	Australia	2145
6	Wollongong Hospital	Wollongong	Australia	2500
7	Hospital Erasto Gaertner- Liga Paranaense de Combate ao Câncer	Curitiba	Brazil	81520-060
8	Cepon - Centro De Pesquisas Oncologicas	Florianopolis	Brazil	88034-000
9	Liga Norte Riograndense Contra O Cancer	Natal	Brazil	59062-000
10	Hospital de Clínicas de Porto Alegre	Porto Alegre	Brazil	90035-903
11	Instituto do cancer -COR -Hospital Mae de Deus	Porto Alegre	Brazil	90110-270
12	Oncoclínicas	Rio De Janeiro	Brazil	22250-905
13	Hospital de Base de São José do Rio Preto	São José do Rio Preto	Brazil	15090-000
14	Hospital Paulistano	São Paulo	Brazil	01321-001
15	Instituto D'Or de Pesquisa e Ensino (IDOR)	São Paulo	Brazil	4501000
16	CHU d'Angers	Angers	France	49933
17	Hopital Saint Vincent de Paul	Lille	France	59020
18	CHU de Limoges, Hopital Dupuytren	Limoges	France	87042
19	Hôpital de La Conception	Marseille	France	13005
20	CHU de Nice Hopital de l Archet	Nice	France	06200
21	Hopital Saint-Louis	Paris Cedex 10	France	75475
22	Hopital Cochin APHP	Paris, 75	France	75674
23	CHRU Tours Hôpital Bretonneau	Tours	France	37000
24	CHU de Nancy_ Hôpital Brabois	Vandoeuvre Les Nancy	France	54500
25	Universitatsklinikum Carl Gustav Carcus Dresden	Dresden	Germany	01307
26	Universitätsklinik Freiburg	Freiburg Im Breisgau	Germany	79106
27	Medizinische Hochschule Hannover	Hannover	Germany	30625
28	Universitatsklinikum Leipzig	Leipzig	Germany	04103
29	Klinikum rechts der Isar an der Technischen Universität München	München	Germany	81675
30	Universitaetsklinikum Ulm	Ulm	Germany	89081
31	Policlinico Sant'Orsola Malpighi	Bologna	Italy	40138
32	Azienda Ospedaliero Universitaria di Ferrara	Cona	Italy	44124
33	Università del Piemonte Orientale - Ospedale Maggiore della Carità di Novara	Novara	Italy	28100
34	Aou San Luigi Gonzaga	Orbassano	Italy	10043
35	Grande Ospedale Metropolitano 'Bianchi-Melacrino-Morelli' Reggio Calabria	Reggio Calabria	Italy	89124
36	Fondazione Policlinico Tor Vergata	Roma	Italy	00133
37	Policlinico Umberto I	Roma	Italy	00161
38	Istituto Clinico Humanitas	Rozzano	Italy	20089
39	Emergency Hospital of Dzerzhinsk	Dzerzhinsk	Russian Federation	606019
40	S.P. Botkin Moscow City Clinical Hospital	Moscow	Russian Federation	125284
41	Nizhniy Novgorod Region Clinical Hospital	Nizhny Novgorod	Russian Federation	603126
42	Ryazan Regional Clinical Hospital	Ryazan	Russian Federation	390039
43	Saint Petersburg City Hospital #15	Saint-Petersburg	Russian Federation	123182
44	Clinical Research Institute of Hematology and Transfusiology	St-Petersburg	Russian Federation	191024
45	St.-Petersburg City Clinical Hospital nr 31	St. Petersburg	Russian Federation	197110
46	Oncology Dispensary of Komi Republic	Syktyvkar	Russian Federation	167904
47	King Fahad Specialist hospital	Dammam	Saudi Arabia	15215
48	King Abdulaziz Medical City	Jeddah	Saudi Arabia	21423
49	King Faisal Specialist Hospital & Research Center	Riyadh	Saudi Arabia	12713
50	Hosp. Univ. Germans Trias I Pujol	Badalona	Spain	08916
51	Hosp. Univ. Vall D Hebron	Barcelona	Spain	08035
52	Hosp. de La Santa Creu I Sant Pau	Barcelona	Spain	08041
53	Inst. Cat. Doncologia-H Duran I Reynals	Barcelona	Spain	08908
54	Hosp. Univ. Infanta Leonor	Madrid	Spain	28031
55	Centro Integral Oncológico Clara Campal	Madrid	Spain	28050
56	Hosp. Univ. Son Espases	Palma	Spain	7120
57	Hosp. Clinico Univ. de Salamanca	Salamanca	Spain	37007
58	Hosp. Virgen Del Rocio	Sevilla	Spain	41013
59	INSELSPITAL, Universitätsspital Bern	Bern	Switzerland	3010
60	Hopitaux Universitaires de Geneve	Geneve	Switzerland	1205
61	UniversitaetsSpital Zuerich	Zürich	Switzerland
62	Gulhane Egitim ve Arastirma Hastanesi	Ankara	Turkey	06010
63	Dr.Abdurrahman Yurtaslan Oncology Training and Research Hospital	Ankara	Turkey	06200
64	Ankara Universitesi Tip Fakultesi	Ankara	Turkey	06590
65	Koc Universitesi Hastanesi	Istanbul	Turkey	34010
66	Ege Universitesi Tip Fakultesi	Izmir	Turkey	35100
67	Dokuz Eylul Universitesi Tip Fakultesi	Izmir	Turkey	35340
68	Ondokuz Mayis Universitesi Tip Fakultesi	Samsun	Turkey	55200
69	St James Hospital	Leeds	United Kingdom	LS9 7TF
70	University College London Hospitals	London	United Kingdom	NW1 2BU
71	Kings College Hospital	London	United Kingdom	SE5 9RF
72	Royal Victoria Infirmary	Newcastle Upun Tyne	United Kingdom	NE1 4LP
73	Churchill Hospital	Oxford	United Kingdom	OX3 7LE