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)
- Conditions
- Myelodysplastic SyndromesLeukemia, Myelomonocytic, Chronic
- Interventions
- Registration Number
- NCT04264806
- Lead Sponsor
- Janssen Research & Development, LLC
- 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).
- 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.
Recruitment & Eligibility
- Status
- WITHDRAWN
- Sex
- All
- Target Recruitment
- Not specified
- 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)
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Azacitidine: Participants with MDS or CMML Azacitidine 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. Azacitidine and Cusatuzumab: Participants with MDS or CMML Azacitidine 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. Azacitidine and Cusatuzumab: Participants with MDS or CMML Cusatuzumab 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.
- Primary Outcome Measures
Name Time Method 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
Name Time Method Percentage of Participants Achieving Complete Remission (CR) Up to 4 years Percentage of participants achieving CR as per IWG criteria will be reported.
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.
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.
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.
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.
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.
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.
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.
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.
Trial Locations
- Locations (73)
King Faisal Specialist Hospital & Research Center
🇸🇦Riyadh, Saudi Arabia
UniversitaetsSpital Zuerich
🇨🇭Zürich, Switzerland
St Vincents Hospital Sydney
🇦🇺Darlinghurst, Australia
Dr.Abdurrahman Yurtaslan Oncology Training and Research Hospital
🇹🇷Ankara, Turkey
St Vincents Hospital Melbourne
🇦🇺Fitzroy, Australia
Peter MacCallum Cancer Institute
🇦🇺Melbourne, Australia
Royal Perth Hospital
🇦🇺Perth, Australia
Westmead Hospital
🇦🇺Westmead, Australia
Cepon - Centro De Pesquisas Oncologicas
🇧🇷Florianopolis, Brazil
Wollongong Hospital
🇦🇺Wollongong, Australia
Hospital Erasto Gaertner- Liga Paranaense de Combate ao Câncer
🇧🇷Curitiba, Brazil
Liga Norte Riograndense Contra O Cancer
🇧🇷Natal, Brazil
Hospital de Clínicas de Porto Alegre
🇧🇷Porto Alegre, Brazil
Instituto do cancer -COR -Hospital Mae de Deus
🇧🇷Porto Alegre, Brazil
Oncoclínicas
🇧🇷Rio De Janeiro, Brazil
Hospital Paulistano
🇧🇷São Paulo, Brazil
Instituto D'Or de Pesquisa e Ensino (IDOR)
🇧🇷São Paulo, Brazil
Hospital de Base de São José do Rio Preto
🇧🇷São José do Rio Preto, Brazil
Hopital Saint Vincent de Paul
🇫🇷Lille, France
CHU d'Angers
🇫🇷Angers, France
CHU de Limoges, Hopital Dupuytren
🇫🇷Limoges, France
CHU de Nice Hopital de l Archet
🇫🇷Nice, France
Hopital Saint-Louis
🇫🇷Paris Cedex 10, France
Hôpital de La Conception
🇫🇷Marseille, France
Hopital Cochin APHP
🇫🇷Paris, 75, France
CHRU Tours Hôpital Bretonneau
🇫🇷Tours, France
CHU de Nancy_ Hôpital Brabois
🇫🇷Vandoeuvre Les Nancy, France
Universitatsklinikum Carl Gustav Carcus Dresden
🇩🇪Dresden, Germany
Universitätsklinik Freiburg
🇩🇪Freiburg Im Breisgau, Germany
Klinikum rechts der Isar an der Technischen Universität München
🇩🇪München, Germany
Medizinische Hochschule Hannover
🇩🇪Hannover, Germany
Universitatsklinikum Leipzig
🇩🇪Leipzig, Germany
Universitaetsklinikum Ulm
🇩🇪Ulm, Germany
Policlinico Sant'Orsola Malpighi
🇮🇹Bologna, Italy
Azienda Ospedaliero Universitaria di Ferrara
🇮🇹Cona, Italy
Università del Piemonte Orientale - Ospedale Maggiore della Carità di Novara
🇮🇹Novara, Italy
Aou San Luigi Gonzaga
🇮🇹Orbassano, Italy
Grande Ospedale Metropolitano 'Bianchi-Melacrino-Morelli' Reggio Calabria
🇮🇹Reggio Calabria, Italy
Fondazione Policlinico Tor Vergata
🇮🇹Roma, Italy
Policlinico Umberto I
🇮🇹Roma, Italy
Emergency Hospital of Dzerzhinsk
🇷🇺Dzerzhinsk, Russian Federation
Istituto Clinico Humanitas
🇮🇹Rozzano, Italy
S.P. Botkin Moscow City Clinical Hospital
🇷🇺Moscow, Russian Federation
Ryazan Regional Clinical Hospital
🇷🇺Ryazan, Russian Federation
Nizhniy Novgorod Region Clinical Hospital
🇷🇺Nizhny Novgorod, Russian Federation
Saint Petersburg City Hospital #15
🇷🇺Saint-Petersburg, Russian Federation
Clinical Research Institute of Hematology and Transfusiology
🇷🇺St-Petersburg, Russian Federation
St.-Petersburg City Clinical Hospital nr 31
🇷🇺St. Petersburg, Russian Federation
Oncology Dispensary of Komi Republic
🇷🇺Syktyvkar, Russian Federation
Inst. Cat. Doncologia-H Duran I Reynals
🇪🇸Barcelona, Spain
King Fahad Specialist hospital
🇸🇦Dammam, Saudi Arabia
King Abdulaziz Medical City
🇸🇦Jeddah, Saudi Arabia
Hosp. Univ. Germans Trias I Pujol
🇪🇸Badalona, Spain
Hosp. de La Santa Creu I Sant Pau
🇪🇸Barcelona, Spain
Hosp. Univ. Vall D Hebron
🇪🇸Barcelona, Spain
Hosp. Univ. Infanta Leonor
🇪🇸Madrid, Spain
Centro Integral Oncológico Clara Campal
🇪🇸Madrid, Spain
Hosp. Univ. Son Espases
🇪🇸Palma, Spain
Hosp. Clinico Univ. de Salamanca
🇪🇸Salamanca, Spain
Hosp. Virgen Del Rocio
🇪🇸Sevilla, Spain
INSELSPITAL, Universitätsspital Bern
🇨🇭Bern, Switzerland
Hopitaux Universitaires de Geneve
🇨🇭Geneve, Switzerland
Gulhane Egitim ve Arastirma Hastanesi
🇹🇷Ankara, Turkey
Ege Universitesi Tip Fakultesi
🇹🇷Izmir, Turkey
Dokuz Eylul Universitesi Tip Fakultesi
🇹🇷Izmir, Turkey
Ankara Universitesi Tip Fakultesi
🇹🇷Ankara, Turkey
Koc Universitesi Hastanesi
🇹🇷Istanbul, Turkey
University College London Hospitals
🇬🇧London, United Kingdom
Ondokuz Mayis Universitesi Tip Fakultesi
🇹🇷Samsun, Turkey
Kings College Hospital
🇬🇧London, United Kingdom
St James Hospital
🇬🇧Leeds, United Kingdom
Royal Victoria Infirmary
🇬🇧Newcastle Upun Tyne, United Kingdom
Churchill Hospital
🇬🇧Oxford, United Kingdom