Leukemia, Myeloid, Acute
Conditions
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.
Interventions
DRUGAzacitidine
Azacitidine SC or IV will be administered at a standard dose of 75 mg/m\^2 on days 1-7 of each cycle.
DRUGCusatuzumab
Cusatuzumab IV will be administered as 10 mg/kg or 20 mg/kg on days 3 and 17 of each cycle.
Sponsors
argenx
Janssen Research & Development, LLC
OncoVerity, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 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) |
| 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. |
| 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). |
| 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). |
| 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. |
| 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 |
| Maximum Serum Concentration (Cmax) of Cusatuzumab | Cycle 1 Day 3 | Cmax is the maximum cusatuzumab serum concentration observed at Cycle 1 Day 3. |
| Number of Participants With Anti-cusatuzumab Antibodies | Up to 3 years and 5 months | Number of participants exhibiting anti-drug antibodies for cusatuzumab. |
| 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. |
Countries
Australia, Brazil, France, Israel, Italy, Russia, Spain, Switzerland, Turkey (Türkiye)
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cusatuzumab 10 mg/kg Plus Azacitidine Participants received 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. | 51 |
| Cusatuzumab 20 mg/kg Plus Azacitidine Participants received 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. | 52 |
| Total | 103 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Ongoing treatment at data cutoff | 5 | 9 |
| Overall Study | Randomized but did not receive assigned treatment | 0 | 1 |
Baseline characteristics
| Characteristic | Cusatuzumab 20 mg/kg Plus Azacitidine | Total | Cusatuzumab 10 mg/kg Plus Azacitidine |
|---|---|---|---|
| Age, Continuous | 75 years | 74 years | 74 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 14 Participants | 24 Participants | 10 Participants |
| Race (NIH/OMB) White | 38 Participants | 78 Participants | 40 Participants |
| Region of Enrollment Australia | 4 Participants | 9 Participants | 5 Participants |
| Region of Enrollment France | 10 Participants | 19 Participants | 9 Participants |
| Region of Enrollment Italy | 3 Participants | 8 Participants | 5 Participants |
| Region of Enrollment Russia | 16 Participants | 29 Participants | 13 Participants |
| Region of Enrollment Spain | 7 Participants | 12 Participants | 5 Participants |
| Region of Enrollment Switzerland | 4 Participants | 8 Participants | 4 Participants |
| Region of Enrollment Turkey | 8 Participants | 18 Participants | 10 Participants |
| Sex: Female, Male Female | 23 Participants | 46 Participants | 23 Participants |
| Sex: Female, Male Male | 29 Participants | 57 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 39 / 51 | 30 / 51 |
| other Total, other adverse events | 51 / 51 | 50 / 51 |
| serious Total, serious adverse events | 44 / 51 | 40 / 51 |
Outcome results
Primary
Percentage of Participants With Complete Remission (CR)
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
Time frame: Up to 3 years and 5 months
Population: Intention-to-treat (ITT)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cusatuzumab 10 mg/kg Plus Azacitidine | Percentage of Participants With Complete Remission (CR) | 11.76 percentage of participants |
| Cusatuzumab 20 mg/kg Plus Azacitidine | Percentage of Participants With Complete Remission (CR) | 26.92 percentage of participants |
Secondary
Cusatuzumab Minimum Serum Concentration (Cmin)
Cmin is the minimum cusatuzumab serum concentration observed at Cycle 1 Day 3
Time frame: Cycle 1 Day 3
Population: All participants with available serum concentrations per intervention group.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cusatuzumab 10 mg/kg Plus Azacitidine | Cusatuzumab Minimum Serum Concentration (Cmin) | NA micrograms/milliliter |
| Cusatuzumab 20 mg/kg Plus Azacitidine | Cusatuzumab Minimum Serum Concentration (Cmin) | NA micrograms/milliliter |
Secondary
Duration of First Response
Defined as time from achieving the first response of CR, CRh, or CRi to disease relapse or death from any cause.
Time frame: Up to 3 years and 5 months
Population: Responder population: Participants who achieved CR, CRh or CRi
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cusatuzumab 10 mg/kg Plus Azacitidine | Duration of First Response | 5.6 Months |
| Cusatuzumab 20 mg/kg Plus Azacitidine | Duration of First Response | 13.6 Months |
Secondary
Maximum Serum Concentration (Cmax) of Cusatuzumab
Cmax is the maximum cusatuzumab serum concentration observed at Cycle 1 Day 3.
Time frame: Cycle 1 Day 3
Population: All participants with available serum concentrations per intervention group
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cusatuzumab 10 mg/kg Plus Azacitidine | Maximum Serum Concentration (Cmax) of Cusatuzumab | 224 micrograms/milliliter | Standard Deviation 54.1 |
| Cusatuzumab 20 mg/kg Plus Azacitidine | Maximum Serum Concentration (Cmax) of Cusatuzumab | 458 micrograms/milliliter | Standard Deviation 89.7 |
Secondary
Number of Participants With Anti-cusatuzumab Antibodies
Number of participants exhibiting anti-drug antibodies for cusatuzumab.
Time frame: Up to 3 years and 5 months
Population: Participants with evaluable samples.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cusatuzumab 10 mg/kg Plus Azacitidine | Number of Participants With Anti-cusatuzumab Antibodies | 7 Participants |
| Cusatuzumab 20 mg/kg Plus Azacitidine | Number of Participants With Anti-cusatuzumab Antibodies | 2 Participants |
Secondary
Overall Response Rate (ORR)
ORR is defined as percentage of participants with CR, CRh and CRi based on ELN 2017 response criteria.
Time frame: Up to 3 years and 5 months
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cusatuzumab 10 mg/kg Plus Azacitidine | Overall Response Rate (ORR) | 29.4 percentage of participants |
| Cusatuzumab 20 mg/kg Plus Azacitidine | Overall Response Rate (ORR) | 40.4 percentage of participants |
Secondary
Percentage of Participants With CR Plus CRh
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
Time frame: Up to 3 years and 5 months
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cusatuzumab 10 mg/kg Plus Azacitidine | Percentage of Participants With CR Plus CRh | 21.6 percentage of participants |
| Cusatuzumab 20 mg/kg Plus Azacitidine | Percentage of Participants With CR Plus CRh | 34.6 percentage of participants |
Secondary
Percentage of Participants With CR With Incomplete Recovery (CRi)
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)
Time frame: Up to 3 years and 5 months
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cusatuzumab 10 mg/kg Plus Azacitidine | Percentage of Participants With CR With Incomplete Recovery (CRi) | 7.8 percentage of participants |
| Cusatuzumab 20 mg/kg Plus Azacitidine | Percentage of Participants With CR With Incomplete Recovery (CRi) | 5.8 percentage of participants |
Secondary
Percentage of Participants With CR Without MRD
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 frame: Up to 3 years and 5 months
Population: ITT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cusatuzumab 10 mg/kg Plus Azacitidine | Percentage of Participants With CR Without MRD | 1 Participants |
| Cusatuzumab 20 mg/kg Plus Azacitidine | Percentage of Participants With CR Without MRD | 4 Participants |
Secondary
Percentage of Participants With CR With Partial Hematological Recovery (CRh)
CRh defined as meeting all criteria for CR except ANC \>0.5x10\^9/L and platelet count \>50x10\^9/L
Time frame: Up to 3 years and 5 months
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cusatuzumab 10 mg/kg Plus Azacitidine | Percentage of Participants With CR With Partial Hematological Recovery (CRh) | 9.8 percentage of participants |
| Cusatuzumab 20 mg/kg Plus Azacitidine | Percentage of Participants With CR With Partial Hematological Recovery (CRh) | 7.7 percentage of participants |
Secondary
Percentage of Participants With Negative MRD Who Achieved CR, CRh, CRi, or Morphologic Leukemia-free State (MLFS)
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).
Time frame: Up to 3 years and 5 months
Secondary
Red Blood Cell (RBC) and/or Platelets Transfusion Independence
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.
Time frame: Up to 3 years and 5 months
Population: ITT
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cusatuzumab 10 mg/kg Plus Azacitidine | Red Blood Cell (RBC) and/or Platelets Transfusion Independence | RBC Transfusion Independence | 29.4 percentage of participants |
| Cusatuzumab 10 mg/kg Plus Azacitidine | Red Blood Cell (RBC) and/or Platelets Transfusion Independence | Platelets Transfusion Independence | 39.2 percentage of participants |
| Cusatuzumab 10 mg/kg Plus Azacitidine | Red Blood Cell (RBC) and/or Platelets Transfusion Independence | RBC and Platelets Transfusion Independence | 27.5 percentage of participants |
| Cusatuzumab 20 mg/kg Plus Azacitidine | Red Blood Cell (RBC) and/or Platelets Transfusion Independence | RBC Transfusion Independence | 42.3 percentage of participants |
| Cusatuzumab 20 mg/kg Plus Azacitidine | Red Blood Cell (RBC) and/or Platelets Transfusion Independence | Platelets Transfusion Independence | 51.9 percentage of participants |
| Cusatuzumab 20 mg/kg Plus Azacitidine | Red Blood Cell (RBC) and/or Platelets Transfusion Independence | RBC and Platelets Transfusion Independence | 36.5 percentage of participants |
Secondary
Time to First Response
Defined as time from randomization to achieving the first response of CR, CRh, or CRi.
Time frame: Up to 3 years and 5 months
Population: Responder population: Participants who achieved CR, CRh or CRi
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cusatuzumab 10 mg/kg Plus Azacitidine | Time to First Response | 2.8 Months |
| Cusatuzumab 20 mg/kg Plus Azacitidine | Time to First Response | 3 Months |