A Study of Cusatuzumab Plus Azacitidine in Participants With Newly Diagnosed Acute Myeloid Leukemia Who Are Not Candidates for Intensive Chemotherapy

Phase 2

Active, not recruiting

Conditions: Leukemia, Myeloid, Acute

Interventions: Drug: Azacitidine
Drug: Cusatuzumab

Registration Number: NCT04023526

Lead Sponsor: OncoVerity, Inc.

Brief Summary: The purpose of this study is to determine the efficacy of cusatuzumab in combination with azacitidine in participants with previously untreated acute myeloid leukemia (AML) who are not eligible for intensive chemotherapy.

Detailed Description: AML is a heterogeneous disease characterized by uncontrolled clonal expansion of hematopoietic progenitor cells. As the most common form of acute leukemia, AML accounts for the largest number of annual deaths from leukemia. Over 95 percent (%) of AML blasts harvested from newly diagnosed AML participants expressed Cluster of Differentiation (CD) 70 on the cell surface. Cusatuzumab (JNJ-74494550) is a humanized monoclonal antibody of camelid origin, binding with tight affinity to human CD70. Cusatuzumab has been modified to induce enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) for therapeutic use in participants with cancer. Azacitidine is a pyrimidine nucleoside analogue of cytidine with antineoplastic activity and is indicated for the treatment of adult participants with AML or intermediate 2 and high-risk myelodysplastic syndrome (MDS) with greater than 20% marrow blasts who are not eligible for hematopoietic stem cell transplantation. This study will evaluate 2 doses of cusatuzumab in combination with standard dose azacitidine in participants with AML who are not candidates for intensive chemotherapy (Part 1). Part 1 data will be reviewed by a Data Review Committee to select a preferred dose of cusatuzumab. The study will include a Screening Phase (28 days prior to randomization), a Treatment Phase, and a Follow-up Phase. The study includes evaluations like vital signs, electrocardiogram, spirometry test, serum chemistry and hematology tests.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 103

Inclusion Criteria

Acute myeloid leukemia (AML) according to World Health Organisation (WHO) 2016 criteria and fulfilling all of the following criteria that defines those who are "not candidates for intensive chemotherapy":
1. greater than or equal to (>=)75 years of age or
2. less than (<) 75 years of age with at least one of the following comorbidities: Eastern Cooperative Oncology Group (ECOG) Performance Status of 2; Severe cardiac comorbidity defined as congestive heart failure or ejection fraction less than or equal to (<=) 50 percent (%); Severe pulmonary comorbidity defined as documented pulmonary disease with lung diffusing capacity for carbon monoxide (DLCO) <=65% of expected, or forced expiratory volume in 1 second (FEV1) <=65% of expected or dyspnea at rest requiring oxygen; Moderate hepatic impairment defined according to NCI organ dysfunction classification criteria (total bilirubin >=1.5 up to 3 times upper limit of normal [ULN]); Creatinine clearance <45 milliliter per minute per 1.73 meter square (mL/ min/1.73 m^2); Comorbidity that, in the Investigator's opinion, makes the participant unsuitable for intensive chemotherapy and must be documented and approved by the Sponsor before randomization
De novo or secondary AML
Previously untreated AML (except: emergency leukapheresis, hydroxyurea, and/or 1 dose of cytarabine [example: 1-2 gram per meter square {g/m^2}] during the Screening Phase to control hyperleukocytosis. These treatments must be discontinued >=24 hours prior to start of study drug). Empiric all trans retinoic acid (ATRA) treatment for presumed acute promyelocytic leukemia (APL) is permitted but APL must be ruled out and ATRA must be discontinued >=24 hours prior to the start of study drug
Not eligible for an allogeneic hematopoietic stem cell transplantation
ECOG Performance Status score of 0, 1 or 2

Exclusion Criteria

Acute promyelocytic leukemia
Leukemic involvement or clinical symptoms of leukemic involvement of the central nervous system
Use of immune suppressive agents for the past 4 weeks before the first administration of cusatuzumab on Cycle 1 Day 3. For regular use of systemic corticosteroids, participants may only be included if free of systemic corticosteroids for a minimum of 5 days before the first administration of cusatuzumab. Treatment of adrenal insufficiency with physiologic replacement doses of corticosteroids are allowed
Prior treatment with a hypomethylating agent for treatment of AML or myelodysplastic syndrome (MDS)
Active malignancies (that is, progressing or requiring treatment in the last 24 months) other than the disease being treated under the study
Any active systemic infection
Known allergies, hypersensitivity, or intolerance to cusatuzumab or azacitidine or its excipients (that is, mannitol, an excipient of azacitidine)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Azacitidine 75 mg/m^2 and Cusatuzumab 10 mg/kg	Cusatuzumab	Participants will receive azacitidine 75 milligram per meter square (mg/m\^2) subcutaneously (SC) or intravenously (IV) on Day 1 through Day 7 and cusatuzumab 10 milligram per kilogram (mg/kg) IV on Day 3 and Day 17 of each 28-day cycle in Part 1. Part 1 findings will be reviewed by a data review committee.
Azacitidine 75 mg/m^2 and Cusatuzumab 20 mg/kg	Azacitidine	Participants will receive azacitidine 75 mg/m\^2 SC or IV on Day 1 through Day 7 and cusatuzumab 20 mg/kg IV on Day 3 and Day 17 of each 28-day cycle in Part 1. Part 1 findings will be reviewed by a data review committee.
Azacitidine 75 mg/m^2 and Cusatuzumab 10 mg/kg	Azacitidine	Participants will receive azacitidine 75 milligram per meter square (mg/m\^2) subcutaneously (SC) or intravenously (IV) on Day 1 through Day 7 and cusatuzumab 10 milligram per kilogram (mg/kg) IV on Day 3 and Day 17 of each 28-day cycle in Part 1. Part 1 findings will be reviewed by a data review committee.
Azacitidine 75 mg/m^2 and Cusatuzumab 20 mg/kg	Cusatuzumab	Participants will receive azacitidine 75 mg/m\^2 SC or IV on Day 1 through Day 7 and cusatuzumab 20 mg/kg IV on Day 3 and Day 17 of each 28-day cycle in Part 1. Part 1 findings will be reviewed by a data review committee.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Complete Remission (CR)	Up to 3 years and 5 months	Complete remission based on European Leukemia Network (ELN) 2017 response criteria. Defined as bone marrow blasts \<5%; absence of circulating blasts and blasts with Auer rods; absences of extramedullary disease; ANC \>= 1.0 x10\^9/L; platelet count \>=100 x 10\^9/L

Secondary Outcome Measures

Name	Time	Method
Maximum Serum Concentration (Cmax) of Cusatuzumab	Cycle 1 Day 3	Cmax is the maximum cusatuzumab serum concentration observed at Cycle 1 Day 3.
Percentage of Participants With CR With Partial Hematological Recovery (CRh)	Up to 3 years and 5 months	CRh defined as meeting all criteria for CR except ANC \>0.5x10\^9/L and platelet count \>50x10\^9/L
Duration of First Response	Up to 3 years and 5 months	Defined as time from achieving the first response of CR, CRh, or CRi to disease relapse or death from any cause.
Percentage of Participants With CR With Incomplete Recovery (CRi)	Up to 3 years and 5 months	CRi based on ELN 2017 response criteria. Defined as meeting all CR criteria except for residual neutropenia (ANC \<1.0x10\^9/L) or thrombocytopenia (platelets \<100x10\^9/L)
Percentage of Participants With CR Without MRD	Up to 3 years and 5 months	CR without minimal residual disease (MRD) defined as less than 1 blast or leukemic stem cell in 1,000 leukocytes (MRD level \<10\^-3 by flow cytometry).
Time to First Response	Up to 3 years and 5 months	Defined as time from randomization to achieving the first response of CR, CRh, or CRi.
Red Blood Cell (RBC) and/or Platelets Transfusion Independence	Up to 3 years and 5 months	Defined as a period of at least 56 consecutive days with no transfusion of RBC and/or platelets between first dose of study drug and the last dose of study drug +30 days.
Cusatuzumab Minimum Serum Concentration (Cmin)	Cycle 1 Day 3	Cmin is the minimum cusatuzumab serum concentration observed at Cycle 1 Day 3
Percentage of Participants With CR Plus CRh	Up to 3 years and 5 months	CR plus CRh based on ELN 2017 response criteria. CR defined as bone marrow blasts \<5%; absence of circulating blasts and blasts with Auer rods; absences of extramedullary disease; ANC \>= 1.0 x10\^9/L; platelet count \>=100 x 10\^9/L CRh defined as meeting all criteria for CR except ANC \>0.5x10\^9/L and platelet count \>50x10\^9/L
Percentage of Participants With Negative MRD Who Achieved CR, CRh, CRi, or Morphologic Leukemia-free State (MLFS)	Up to 3 years and 5 months	Percentage of participants with negative MRD who achieved CR, CRh, CRi, or MLFS will be reported and is defined as less than (\<) 1 blast or leukemic stem cell in 1,000 leukocytes (MRD level \<10\^-3).
Number of Participants With Anti-cusatuzumab Antibodies	Up to 3 years and 5 months	Number of participants exhibiting anti-drug antibodies for cusatuzumab.
Overall Response Rate (ORR)	Up to 3 years and 5 months	ORR is defined as percentage of participants with CR, CRh and CRi based on ELN 2017 response criteria.

Trial Locations

Locations (56): St Vincents Hospital Sydney
🇦🇺
Darlinghurst, Australia
St Vincents Hospital Melbourne
🇦🇺
Fitzroy, Australia
The Alfred Hospital
🇦🇺
Melbourne, Australia
Royal Perth Hospital
🇦🇺
Perth, Australia
Westmead Hospital
🇦🇺
Westmead, Australia
Universidade Estadual De Campinas
🇧🇷
Campinas, Brazil
Hospital das Clinicas de Porto Alegre
🇧🇷
Porto Alegre, Brazil
CHU d'Angers
🇫🇷
Angers, France
CHU Grenoble
🇫🇷
Grenoble cedex 9, France
Institut Paoli Calmettes
🇫🇷
Marseille Cedex 9, France
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St Vincents Hospital Sydney
🇦🇺Darlinghurst, Australia