An Efficacy and Safety Study of Decitabine (DACOGEN) Plus Talacotuzumab (JNJ-56022473; Anti CD123) Versus Decitabine (DACOGEN) Alone in Participants With Acute Myeloid Leukemia (AML) Ineligible for Intensive Chemotherapy

• ClinicalTrials.gov Identifier: NCT02472145
• Recruitment Status: Completed
• First Posted: June 15, 2015
• Results First Posted: February 28, 2019
• Last Update Posted: March 19, 2019
• Sponsor: Janssen Research & Development, LLC
• Information provided by (Responsible Party): Janssen Research & Development, LLC

Tracking Information

• First Submitted Date: April 29, 2015
• First Posted Date: June 15, 2015
• Results First Submitted Date: January 24, 2019
• Results First Posted Date: February 28, 2019
• Last Update Posted Date: March 19, 2019
• Actual Study Start Date: August 4, 2015
• Actual Primary Completion Date: January 25, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 27, 2019)

• Part B: Percentage of Participants Who Achieved Complete Response (Complete Response Rate) Based on Investigator Assessment [ Time Frame: Approximately up to 2.5 years ]
  Complete response rate defined as percentage of participants who achieved complete response as per modified International Working Group (IWG) criteria. CR: Bone marrow blasts less than (<)5 percent (%); absence of blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count greater than (>)1.0*10^9/liter (L) (1000/micro liter [mcL]); platelet count >100*10^9/L (100 000/mcL); independence of red cell transfusions. This endpoint is reported here for Part B only as per the planned analysis.
• Part B: Overall Survival [ Time Frame: Approximately up to 2.5 years ]
  Overall Survival (OS) was defined as the time from the date of randomization to date of death from any cause. Median Overall Survival was estimated by using the Kaplan-Meier method. This endpoint is reported here for Part B only as per the planned analysis.

Original Primary Outcome Measures (submitted: June 10, 2015)

Event-Free Survival [ Time Frame: Up to 1 year after last participant enrolled ]

Time from randomization to treatment failure, relapse from CR (complete response) or CRi (complete response with incomplete recovery), or death of any causes.

Current Secondary Outcome Measures (submitted: February 27, 2019)

• Part B: Event-free Survival (EFS) Based on Investigator Assessment [ Time Frame: Approximately up to 2.5 years ]
  EFS defined as time from randomization to treatment failure, relapse from CR/CRi, or death from any cause, whichever occurs first, per modified IWG criteria. Treatment failure: >25% absolute increase in the bone marrow blast count from baseline to present assessment (example, 20% to 46%) on bone marrow aspirate (or biopsy in case of dry tap); Relapse: Bone marrow blasts greater than equal to (>=)5%; reappearance of blasts in blood; or development of extramedullary disease; CR: Bone marrow blasts <5 %; absence of blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count > 1.0*10^9/L (1000/mcL); platelet count >100*10^9/L (100 000/mcL);independence of red cell transfusions; CRi: Bone marrow blasts <5 %; absence of blasts with Auer rods; absence of extramedullary disease; residual neutropenia <1.0*10^9/L (1000/mcL) or thrombocytopenia <100*10^9/L (100 000/mcL); independence of red cell transfusions. Endpoint reported is for Part B only as per planned analysis.
• Part B: Percentage of Participants Who Achieved CR and CRi (Overall Response Rate) [ Time Frame: Approximately up to 2.5 years ]
  Percentage of participants who achieved CR and CRi, as per modified IWG criteria. CR: Bone marrow blasts less than (<)5 %; absence of blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count greater than (>)1.0 *10^9/liter (L) (1000/ mcL); platelet count >100 *10^9/L (100 000/mcL); independence of red cell transfusions; CRi: Bone marrow blasts <5 %; absence of blasts with Auer rods; absence of extramedullary disease; residual neutropenia <1.0*10^9/L (1000/mcL) or thrombocytopenia <100*10^9/L (100 000/mcL); independence of red cell transfusions. This endpoint is reported here for Part B only as per the planned analysis.
• Part B: Percentage of Participants With Complete Response (CR) Plus Minimal Residual Disease (MRD) Negative Complete Response With Incomplete Recovery (CRi) [ Time Frame: Approximately 2.5 years ]
  Percentage of participants who achieved CR plus MRD-negative CRi were reported. MRD negativity defined as <1 blast or leukemic stem cell in 10,000 leukocytes (MRD level <10^4).CR: Bone marrow blasts less than (<)5 percent (%); absence of blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count greater than (>)1.0*10^9/liter (L) (1000/mcL); platelet count >100*10^9/L (100 000/mcL); independence of red cell transfusions; CRi: Bone marrow blasts <5 %; absence of blasts with Auer rods; absence of extramedullary disease; residual neutropenia <1.0*10^9/L (1000/mcL) or thrombocytopenia <100*10^9/L (100 000/mcL); independence of red cell transfusions. This endpoint is reported here for Part B only as per the planned analysis.
• Part B: Time to Best Response [ Time Frame: Approximately 2.5 years ]
  Time to best response is calculated as the time from the randomization date to the first documented date for the best response for participants who achieved CR or CRi, as per modified IWG criteria. CR: Bone marrow blasts less than (<)5 %; absence of blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count greater than (>)1.0 *10^9/liter (L) (1000/mcL); platelet count >100*10^9/L (100 000/mcL); independence of red cell transfusions; CRi: Bone marrow blasts <5 %; absence of blasts with Auer rods; absence of extramedullary disease; residual neutropenia <1.0*10^9/L (1000/mcL) or thrombocytopenia <100*10^9/L (100 000/mcL); independence of red cell transfusions. This endpoint is reported here for Part B only as per the planned analysis.
• Part B: Duration of Response (DOR) Based on Investigator Assessment [ Time Frame: Approximately 2.5 years ]
  DOR defined as number of weeks from documented best response (CR or CRi) for participants who achieved CR or CRi to relapse, death due to relapse, date of censoring. As per modified IWG criteria: CR: Bone marrow blasts <5 %; absence of blasts with Auer rods; absence of extramedullary disease;absolute neutrophil count >1.0*10^9/L (1000/mcL); platelet count >100*10^9/L (100 000/mcL); independence of red cell transfusions; CRi: Bone marrow blasts <5 %; absence of blasts with Auer rods; absence of extramedullary disease; residual neutropenia <1.0* 10^9/L (1000/mcL) or thrombocytopenia <100*10^9/L (100 000/mcL); independence of red cell transfusions. This endpoint is reported here for Part B only as per the planned analysis.

Original Secondary Outcome Measures (submitted: June 10, 2015)

• Overall response rate (ORR) [ Time Frame: Up to 1 year after last participant enrolled ]
  Percentage of participants achieving CR or CRi.
• Overall Survival (OS) [ Time Frame: Up to 1 year after last participant enrolled ]
  Time from randomization to death from any cause.
• Relapse-free survival (RFS) [ Time Frame: Up to 1 year after last participant enrolled ]
  For participants who achieved CR or CRi, time from achieving CR or CRi to relapse or death from any cause.
• Number of Participants With Adverse Event [ Time Frame: Up to 1 year after last participant enrolled ]
• Number of Participants With Anti-drug Antibody at any Visit [ Time Frame: Up to 1 year after last participant enrolled ]
• Functional Assessment of Cancer Therapy -Leukemia (FACT-Leu) Score [ Time Frame: Up to 1 year after last participant enrolled ]
  A 44-item, self-reported leukemia-specific measure that is used to quantitatively assess an individual's perception of how the disease affects their day-to-day life.
• European Quality of Life- 5 Dimension 5-Level (EQ-5D-5L) Score [ Time Frame: Baseline and 1 year after last participant enrolled ]
  A generic measure of health status with a 5 item questionnaire that assesses 5 domains including mobility, self-care, usual activities, pain/discomfort and anxiety/depression plus a visual analog scale rating of "health today".
• Area under the concentration-time curve between time t1 and t2 (AUC t1-t2) [ Time Frame: Pt A:Predose (Day 1 of cyc 1,2; Day 8 of cyc 3, 5),postdose (30 min,Day 2,3,4,8 of cyc 1;Pt B1:Predose (Day 1,5 min prior end of inf),postdose (1 h of cyc 1,4); Pt B2:Predose (Day 1,8 of cyc 1,2,4, Day 22 of cyc 1,4),postdose (30 min,Day 9,23 of cyc 1,4) ]
• Total Systemic Clearance (CL) [ Time Frame: Pt A:Predose (Day 1 of cyc 1,2; Day 8 of cyc 3, 5),postdose (30 min,Day 2,3,4,8 of cyc 1;Pt B1:Predose (Day 1,5 min prior end of inf),postdose (1 h of cyc 1,4); Pt B2:Predose (Day 1,8 of cyc 1,2,4, Day 22 of cyc 1,4),postdose (30 min,Day 9,23 of cyc 1,4) ]
• Maximum Observed Serum Concentration (Cmax) [ Time Frame: Pt A:Predose (Day 1 of cyc 1,2; Day 8 of cyc 3, 5),postdose (30 min,Day 2,3,4,8 of cyc 1;Pt B1:Predose (Day 1,5 min prior end of inf),postdose (1 h of cyc 1,4); Pt B2:Predose (Day 1,8 of cyc 1,2,4, Day 22 of cyc 1,4),postdose (30 min,Day 9,23 of cyc 1,4) ]
• Minimum Observed Concentration (Cmin) [ Time Frame: Pt A:Predose (Day 1 of cyc 1,2; Day 8 of cyc 3, 5),postdose (30 min,Day 2,3,4,8 of cyc 1;Pt B1:Predose (Day 1,5 min prior end of inf),postdose (1 h of cyc 1,4); Pt B2:Predose (Day 1,8 of cyc 1,2,4, Day 22 of cyc 1,4),postdose (30 min,Day 9,23 of cyc 1,4) ]
• Volume of Distribution [ Time Frame: Pt A:Predose (Day 1 of cyc 1,2; Day 8 of cyc 3, 5),postdose (30 min,Day 2,3,4,8 of cyc 1;Pt B1:Predose (Day 1,5 min prior end of inf),postdose (1 h of cyc 1,4); Pt B2:Predose (Day 1,8 of cyc 1,2,4, Day 22 of cyc 1,4),postdose (30 min,Day 9,23 of cyc 1,4) ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: An Efficacy and Safety Study of Decitabine (DACOGEN) Plus Talacotuzumab (JNJ-56022473; Anti CD123) Versus Decitabine (DACOGEN) Alone in Participants With Acute Myeloid Leukemia (AML) Ineligible for Intensive Chemotherapy
• Official Title: A Randomized Phase 2/3 Study of DACOGEN® (Decitabine) Plus Talacotuzumab (JNJ-56022473; Anti CD123) Versus DACOGEN (Decitabine) Alone in Patients With AML Who Are Not Candidates for Intensive Chemotherapy
• Brief Summary: The primary objective of study Part A is to assess the safety of talacotuzumab (formerly CSL362) monotherapy and confirm the recommended Phase 2 dose (RP2D) in participants with acute myeloid leukemia (AML) for whom experimental therapy is appropriate. The primary objective of study Part B are to assess complete response (CR) rate and overall survival (OS) in participants with AML who are not eligible for intense induction chemotherapy and who are randomly assigned to receive decitabine plus talacotuzumab at the RP2D or decitabine alone.
• Detailed Description: This is a 2-part, open-label, multicenter, Phase 2/3 study conducted in participants with AML who are suitable for experimental therapy (Part A) and in participants with untreated AML who are not eligible for intense induction chemotherapy or hematopoeitic stem cell transplantation (HSCT) (Part B). In Study Part A, the safety, pharmacokinetic (PK) and pharmacodynamic (PD) profile will be assessed to confirm the RP2D of 9 milligram per kilogram (mg/kg) talacotuzumab. In Study Part B, participants will be randomized in a 1:1 ratio into either decitabine + talacotuzumab (arm 1) or decitabine alone (arm 2). Blood and bone marrow sampling will be done in Part A and B for disease assessment, PK, PD, and biomarkers will be collected in all participants. Safety will be monitored throughout the study.
• Study Type: Interventional
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Leukemia, Myeloid, Acute

Intervention

• Drug: Decitabine 20 mg/m^2
  Decitabine 20 milligram per square meter (mg/[m^2]) from Day 1, 2, 3, 4 and 5 of a 28-day cycle.
  Other Name: DACOGEN
• Drug: Talacotuzumab 9 mg/kg
  Talacotuzumab 9 milligram per kilogram mg/kg on Day 8 and 22 of a 28-day cycle.
  Other Name: CSL362

Study Arms

• Experimental: Decitabine plus Talacotuzumab

  Part A: For Cycle 1 of Part A, participants will receive talacotuzumab on Day 1. Starting from Cycle 2 of Part A, participants may receive decitabine on Day 1, 2, 3, 4, and 5, and talacotuzumab on Day 8 and 22 of a 28-day cycle.

  Part B Arm 1: Participants will receive decitabine on Day 1, 2, 3, 4, and 5, and talacotuzumab on Day 8 and 22 of a 28-day cycle.

  Interventions:

  • Drug: Decitabine 20 mg/m^2
  • Drug: Talacotuzumab 9 mg/kg
• Active Comparator: Decitabine
  Participants in Part B Arm 2 will receive decitabine on Day 1,2, 3, 4 and 5 of a 28-day cycle.
  Intervention: Drug: Decitabine 20 mg/m^2

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 14, 2017): 326
• Original Estimated Enrollment (submitted: June 10, 2015): 126
• Actual Study Completion Date: January 25, 2018
• Actual Primary Completion Date: January 25, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• De novo or secondary acute myeloid leukemia (AML) (post myelodysplastic syndrome [MDS] or myeloproliferative neoplasm [MPN] or after leukemogenic chemotherapy) according to WHO 2008 criteria

For Part A:

- Participants With AML: treatment naive or relapsed for whom experimental therapy is appropriate (as assessed by their treating physician)

For Part B:

• Greater than or equal to (>=) 75 years of age or >= 65 up to 75 years of age and have at least one of the following: congestive heart failure or ejection fraction less than or equal to (<=) 50 percent; creatinine greater than (>) 2 milligram per deciliter (mg/dL); dialysis or prior renal transplant; documented pulmonary disease with lung diffusing capacity for carbon monoxide (DLCO) <= 65 percent of expected, or forced expiratory volume in 1 second (FEV1) <= 65 percent of expected or dyspnea at rest requiring oxygen; eastern cooperative oncology group (ECOG) performance status of 2; prior or current malignancy that does not require concurrent treatment; unresolved infection; 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
• Previously untreated AML (except: emergency leukopheresis and/or hydroxyurea during the screening phase to control hyperleukocytosis but must be discontinued at least one day prior to start of study therapy)
• Not eligible for an allogeneic hematopoietic stem cell transplantation
• ECOG Performance Status score of 0, 1 or 2
• A woman must be either: Not of childbearing potential: postmenopausal (more than [>] 45 years of age with amenorrhea for at least 12 months; If, of childbearing potential must be practicing a highly effective method of birth control
• A woman of childbearing potential must have a negative serum (beta-human chorionic gonadotropin [beta-hCG]) or urine pregnancy test at screening
• A man who is sexually active with a woman of childbearing potential and has not had a vasectomy must agree to use a barrier method of birth control eg, either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository for at least 3 months after last study treatment

Exclusion Criteria:

• Acute promyelocytic leukemia with t(15;17), or its molecular equivalent (PML-RARalpha)
• For Part B only: Known leukemic involvement or clinical symptoms of leukemic involvement of the central nervous system
• Participants who received prior treatment with a hypomethylating agent
• For Part A only: Participants who did not recover from all clinically significant toxicities (excluding alopecia and hematologic toxicities) of any previous surgery, radiotherapy, targeted therapy, or chemotherapy to less than or equal to Grade 1
• Any uncontrolled active systemic infection that requires treatment with intravenous (IV) antibiotics
• A history of human immunodeficiency virus (HIV) antibody positive or tests positive for HIV if tested at screening
• Active systemic hepatitis infection requiring treatment or other clinically active liver disease

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 65 Years and older (Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Belgium, France, Germany, Israel, Korea, Republic of, Poland, Russian Federation, Spain, Sweden, Taiwan, Turkey, United Kingdom, United States
• Removed Location Countries: Brazil, Italy

Administrative Information

• NCT Number: NCT02472145
• Other Study ID Numbers: CR107273; 56022473AML2002 ( Other Identifier: Janssen Research & Development, LLC ); 2015-001611-12 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Responsible Party: Janssen Research & Development, LLC
• Study Sponsor: Janssen Research & Development, LLC
• Collaborators: Not Provided

Investigators

• Study Director: Janssen Research & Development, LLC Clinical Trial; Janssen Research & Development, LLC

• PRS Account: Janssen Research & Development, LLC
• Verification Date: March 2019