A Study of Decitabine (DACOGEN) in Sequential Administration With Cytarabine in Children With Relapsed or Refractory Acute Myeloid Leukemia

NCT01853228 | Terminated Phase 1 Results DMC

• 3 other identifiers: CR102071DACOGENAML20042013-000390-70
• Study Type: interventional
• Target: 17
• Locations: 7 countries
• Sites: 17

Brief Summary

The purpose of this study is to examine the safety and efficacy of decitabine in sequential administration with cytarabine in children with relapsed or refractory acute myeloid leukemia (AML).

Conditions

Acute Myeloid Leukemia

Keywords

Acute myeloid leukemia; Relapsed or refractory acute myeloid leukemia; Children; Decitabine; DACOGEN; Cytarabine

Outcome Measures

Primary Outcomes (6)

• Phase 1: Maximum Tolerated Dose (MTD) of Cytarabine

  The maximum tolerated dose (MTD) for cytarabine was based on the number of participants experiencing a dose-limiting toxicity (DLT) by the end of Cycle 1. A non-hematological DLT was defined as: any Grade \>=3 toxicity that persists for greater than (\>) 5 days or any Grade 2 toxicity that persists for \>7 days and that is intolerable to the participant. A hematological DLT was defined as Grade 4 neutropenia or thrombocytopenia due to a hypoplastic bone marrow at Day 42, in the absence of malignant infiltration. The nominal duration of each cycle was 28 days. However, participants who had not experienced bone marrow recovery at Day 28 were followed up to Day 42. Failure of marrow recovery (improvement to Grade 3) by Day 42 was considered a DLT. The maximum duration of Cycle 1 was therefore 42 days.

  Cycle 1 (42 days)

• Phase 1 and 2: Total Clearance of Decitabine

  Total clearance of drug after intravenously administration was calculated as: dose/area under the plasma concentration-time curve.

  Cycle 1 (28 days) Day 5: pre-infusion, 0.5 hour during infusion, end of infusion and at 5 minute (min), 0.5 hour, 1 hour, and 2 hour after end of infusion

• Phase 1 and 2: Volume of Distribution at Steady-State (Vss) of Decitabine

  Volume of distribution 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.

  Cycle 1 (28 days) Day 5: pre-infusion, 0.5 hour during infusion, end of infusion and at 5 min, 0.5 hour, 1 hour, and 2 hour after end of infusion

• Phase 2: Percentage of Participants Who Achieved CR or CRi at Cycle 1 Day 28

  Response rate (percentage of participants who achieved CR or CRi) was measured using international working group (IWG) criteria. Response rate is defined as complete remission (CR) or complete remission with incomplete blood count recovery (CRi) in children with relapsed or refractory acute myeloid leukemia. CRi is defined as morphologic CR with residual neutropenia (less than \[\<\] 1,000/microliter) or thrombocytopenia \<100,000/ microliter). CR is defined as morphologic leukemia-free state, with less than 5 percentage (%) blasts in aspirate sample with marrow spicules and with a count of greater than or equal to (\>=) 200 nucleated cells, plus absolute neutrophil count (ANC) greater than (\>) 1,000/ microliter, platelet count of \>100,000/microliter and participant must be independent of transfusions for a minimum of 1 week before each marrow assessment.

  Cycle 1 (28 days) Day 28

• Phase 2: Percentage of Participants Who Achieved CR or CRi at Cycle 2 Day 28

  Response rate (percentage of participants who achieved CR or CRi) was measured using international working group (IWG) criteria. Response rate is defined as complete remission (CR) or complete remission with incomplete blood count recovery (CRi) in children with relapsed or refractory acute myeloid leukemia. CRi is defined as morphologic CR with residual neutropenia (less than \[\<\] 1,000/microliter) or thrombocytopenia \<100,000/ microliter). CR is defined as morphologic leukemia-free state, with less than 5 percentage (%) blasts in aspirate sample with marrow spicules and with a count of greater than or equal to (\>=) 200 nucleated cells, plus absolute neutrophil count (ANC) greater than (\>) 1,000/ microliter, platelet count of \>100,000/microliter and participant must be independent of transfusions for a minimum of 1 week before each marrow assessment.

  Cycle 2 (28 days) Day 28

• Phase 2: Percentage of Participants Who Achieved CR or CRi at End of Study Treatment

  Response rate (percentage of participants who achieved CR or CRi) was measured using international working group (IWG) criteria. Response rate is defined as complete remission (CR) or complete remission with incomplete blood count recovery (CRi) in children with relapsed or refractory acute myeloid leukemia. CRi is defined as morphologic CR with residual neutropenia (less than \[\<\] 1,000/microliter) or thrombocytopenia \<100,000/ microliter). CR is defined as morphologic leukemia-free state, with less than 5 percentage (%) blasts in aspirate sample with marrow spicules and with a count of greater than or equal to (\>=) 200 nucleated cells, plus absolute neutrophil count (ANC) greater than (\>) 1,000/ microliter, platelet count of \>100,000/microliter and participant must be independent of transfusions for a minimum of 1 week before each marrow assessment.

  End of study treatment (approximately 3 years)

Secondary Outcomes (7)

• Phase 1 and 2: Maximum Plasma Concentration (Cmax) of Decitabine

  Cycle 1 (28 days) Day 5: pre-infusion, 0.5 hour during infusion, end of infusion and at 5 min, 0.5 hour, 1 hour, and 2 hour after end of infusion

• Phase 1 and 2: Area Under the Plasma Concentration-Time Curve (AUC) of Decitabine

  Cycle 1 (28 days) Day 5: pre-infusion, 0.5 hour during infusion, end of infusion and at 5 min, 0.5 hour, 1 hour, and 2 hour after end of infusion

• Phase 2: Duration of Response

  From time of response to relapse, study completion/withdrawal, or death, whichever comes first, for up to approximately 3 years 10 months

• Phase 2: Overall Response Rate

  Up to approximately 3 years 10 months

• Phase 1 and 2: Overall Survival (OS)

  From enrollment to death or withdrawal, whichever comes first, for up to approximately 3 years 10 months

Study Arms (1)

Decitabine and cytarabine

EXPERIMENTAL

Drug: Phase1 and Phase 2: decitabine; Drug: Phase 1: cytarabine; Drug: Phase 2: cytarabine

Interventions

Phase1 and Phase 2: decitabine DRUG

20 mg/m2 administered by intravenous infusion over 1 hour once daily for 5 consecutive days (Day 1 to Day 5 of 28-day cycle)

Decitabine and cytarabine

Phase 1: cytarabine DRUG

1 g/m2, 2 g/m2, and 1.5 g/m2 dose levels administered by intravenous infusion over 4 hours daily for 5 consecutive days (Day 8 to Day 12 of 28-day cycle) for the determination of the maximum tolerated dose

Decitabine and cytarabine

Phase 2: cytarabine DRUG

Phase 1 maximum tolerated dose administered by intravenous infusion over 4 hours daily for 5 consecutive days (Day 8 to Day 12 of 28-day cycle)

Decitabine and cytarabine

Eligibility Criteria

• Age: 1 Month - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Histological diagnosis of acute myeloid leukemia (AML) according to the World Health Organization (WHO) classification
• Diagnosis of AML which has relapsed or is refractory to standard of care and no curative therapy exists
• Karnofsky or Lansky score of at least 50
• Must be recovered from acute toxicity of any prior treatment
• Must have adequate organ function according to protocol-defined criteria
• Agrees to protocol-defined use of effective contraception
• Female participants of childbearing potential must have a negative serum or urine pregnancy test at Day 1 of Cycle 1

You may not qualify if:

• Prior treatment with decitabine or azacitidine
• Acute promyelocytic leukemia (M3 subtype in the French-American-British \[FAB\] classification system)
• CNS3 disease
• acute myeloid leukemia (AML) associated with congenital syndromes such as Down syndrome, Fanconi anemia, Bloom syndrome, Kostmann syndrome or Diamond-Blackfan anemia, or bone marrow failure associated with inherited syndromes
• White blood cell count greater than 40x10\^9 cells/liter(L)
• Known allergies, hypersensitivity, or intolerance to decitabine or cytarabine or their excipients
• Contraindications to the use of cytarabine per local prescribing information or prior adverse reactions to cytarabine which would prevent further use
• Currently enrolled in the treatment phase of an interventional investigational study
• Female who is pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study or within 3 months after the last dose of study drug (however, the period after which it becomes safe to become pregnant after the last dose of treatment is not known)
• Male who plans to father a child while enrolled in this study or within 3 months after the last dose of study drug
• Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the patient or that could prevent, limit, or confound the protocol-specified assessments
• Any social or medical condition that in the investigator's opinion renders the participant unfit for study participation
• History of hepatitis B surface antigen (HBsAg) or hepatitis C antibody (anti-HCV) positive, or other clinically active liver disease
• History of human immunodeficiency virus (HIV) antibody positive

Sponsors & Collaborators

• Janssen Research & Development, LLC: lead

Study Sites (17)

Unknown Facility

Ghent, Belgium

Location

Unknown Facility

Copenhagen Ø, Denmark

Location

Unknown Facility

Paris, France

Location

Unknown Facility

Toulouse, France

Location

Unknown Facility

Vandœuvre-lès-Nancy, France

Location

Unknown Facility

Essen, Germany

Location

Unknown Facility

Hamburg, Germany

Location

Unknown Facility

Hanover, Germany

Location

Unknown Facility

Stuttgart, Germany

Location

Unknown Facility

Rotterdam, Netherlands

Location

Unknown Facility

Barcelona, Spain

Location

Unknown Facility

Madrid, Spain

Location

Unknown Facility

Valencia, Spain

Location

Unknown Facility

Birmingham, United Kingdom

Location

Unknown Facility

Cambridge, United Kingdom

Location

Unknown Facility

Glasgow, United Kingdom

Location

Unknown Facility

Sutton, United Kingdom

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Recurrence

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Limitations and Caveats

The Sponsor terminated the study earlier than planned due to lack of efficacy with 8 evaluable participants in Phase 2 with no clinically meaningful anti-leukemic activity.

Results Point of Contact

• Title: Clinical Leader
• Organization: Janssen Research & Development, LLC

ClinicalTrialDisclosure@its.jnj.com

844-434-4210

Study Officials

• Janssen Research & Development, LLC Clinical Trial

  Janssen Research & Development, LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 10, 2013
• First Posted: May 14, 2013
• Study Start: October 22, 2013
• Primary Completion: August 28, 2017
• Study Completion: August 28, 2017
• Last Updated: June 17, 2019
• Results First Posted: June 17, 2019

Record last verified: 2019-03

Locations

NL (1); BE (1); GB (4); FR (3); DE (4); ES (3); DK (1)