Clinical trial NCT00416598: Decitabine as Maintenance Therapy After Standard Therapy in Treating Patients With Previously Untreated Acute Myeloid Leukemia
Official title: Phase II Study of Maintenance Therapy With Decitabine (NSC #127716) Following Standard Induction and Cytogenetic Risk-Adapted Intensification in Previously Untreated Patients With AML &lt; 60 Years
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acute Myeloid Leukemia
Acute Myeloid Leukemia With Myelodysplasia-Related Changes
Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11
Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11
Adult Acute Myeloid Leukemia With t(8;21); (q22; q22.1); RUNX1-RUNX1T1
Adult Acute Myeloid Leukemia With t(9;11)(p22.3;q23.3); MLLT3-KMT2A
Untreated Adult Acute Myeloid Leukemia
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2006-12-28
Enrollment: 546
Sex: ALL
Minimum age (years): 15
Maximum age (years): 59
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This phase II trial is studying the side effects and how well decitabine works when given as maintenance therapy after standard therapy in treating patients with previously untreated acute myeloid leukemia. Drugs used in chemotherapy, such as cytarabine, daunorubicin, etoposide, busulfan, and decitabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving decitabine as maintenance therapy after standard therapy may keep cancer cells from coming back.

Detailed description: PRIMARY OBJECTIVES:

I. To determine the efficacy, feasibility, and toxicities when one year of maintenance therapy with decitabine is given to patients \< 60 years with untreated acute myeloid leukemia (AML) who achieve and maintain first complete remission (CR) following an established induction and intensification regimen.

II. To determine the 1-year disease free survival rate for AML patients in first CR treated with maintenance decitabine.

SECONDARY OBJECTIVES:

I. To measure biologic response to decitabine in evaluable patients with fusion genes to determine eradication of minimal residual disease.

II. To measure surrogates for deoxyribonucleic acid (DNA) demethylation including downregulation of DNA methyltransferase 1 (DNMT1) and induction of fetal hemoglobin.

III. To examine the significance of gene re expression following ex vivo decitabine exposure in primary AML cells taken at the time of diagnosis on clinical outcome and on gene expression at the time of relapse after in vivo decitabine exposure.

IV. To continue to evaluate the effectiveness of a cytogenetically risk-adapted approach for consolidation therapy for patients with core binding factor (CBF) or non-CBF AML.

V. To continue the investigation begun in Cancer and Leukemia Group B (CALGB) 19808 aimed at correlation of the rate of relapse and toxicity with intravenous (IV) busulfan pharmacokinetics when busulfan and etoposide are used as the preparative regimen for autologous stem cell transplantation for AML patients in first CR.

VI. To correlate outcome measures such as complete response (CR), disease-free survival (DFS), event-free survival (EFS), and overall survival (OS), with pretreatment characteristics such as age, sex, race, blood counts, morphology, immunophenotype, cytogenetics, and molecular features of AML.

OUTLINE:

REMISSION INDUCTION THERAPY: Patients receive cytarabine IV over 168 hours on days 1-7 and daunorubicin hydrochloride IV over 5-10 minutes and etoposide IV over 2 hours on days 1-3. Patients undergo bone marrow biopsy on day 14. Patients with residual leukemia proceed to second remission induction therapy. Patients achieving complete remission (CR) proceed to intensification therapy.

SECOND REMISSION INDUCTION THERAPY: Patients receive cytarabine IV over 120 hours on days 1-5 and daunorubicin hydrochloride IV and etoposide IV over 2 hours on days 1 and 2. Patients undergo bone marrow biopsy on day 42. Patients with residual leukemia are removed from the study. Patients achieving CR proceed to intensification therapy.

INTENSIFICATION THERAPY: Patients are stratified and receive intensification therapy according to cytogenetic findings (favorable cytogenetics \[t(8;21)(q22q22), inv(16)(p13;q22), or t(16;16)(p13;q22) by cytogenetic and/or molecular analysis\] vs unfavorable cytogenetics \[all other cytogenetic findings, including normal cytogenetics\]).

FAVORABLE CYTOGENETICS: Within 2-4 weeks after achieving CR, patients receive high-dose cytarabine IV over 3 hours twice daily on days 1, 3, and 5.

Treatment repeats every 28 days for up to 3 courses.

UNFAVORABLE CYTOGENETICS: Peripheral blood stem cell (PBSC) mobilization: Within 2-4 weeks after achieving CR, patients receive etoposide IV over 96 hours and high-dose cytarabine IV over 2 hours twice daily on days 1-4 and filgrastim (G-CSF) subcutaneously (SC) once daily beginning on day 14 and continuing until blood counts recover. Patients then proceed to transplantation.

PBSC OR BONE MARROW TRANSPLANTATION: Patients receive busulfan IV over 2 hours 4 times daily on days -7 to -4 and etoposide IV over 4 hours on day -3. Patients undergo autologous PBSC or bone marrow transplantation on day 0 and receive G-CSF SC once daily beginning on day 0 and continuing until blood counts recover.

UNFAVORABLE CYTOGENETICS AND UNABLE TO UNDERGO PBSC TRANSPLANTATION: Within 2-4 weeks after achieving CR, patients receive etoposide, high-dose cytarabine, and G-CSF as in unfavorable cytogenetics (PBSC mobilization) followed by 2 courses of high-dose cytarabine as in favorable genetics.

MAINTENANCE THERAPY: Within 60-90 days after completion of intensification therapy, patients receive decitabine IV over 1 hour on days 1-5. Treatment repeats every 6 weeks for up to 8 courses.

After completion of study treatment, patients are followed up every 2 months for 1 year, every 6 months for 2 years, and then yearly for 2 years.

Eligibility criteria: Inclusion Criteria:

* Unequivocal histologic diagnosis of AML (\> 20% blasts in the bone marrow based on the World Health Organization \[WHO\] and/or French American British \[FAB\] classifications), excluding M3 (acute promyelocytic leukemia); patients with antecedent myelodysplasia are eligible for treatment on this trial only if there were no bone marrow biopsy showing myelodysplastic syndrome (MDS) \> 3 months prior to enrollment; patients with therapy-related AML are eligible if they have been free of their primary disease and have not received any chemotherapy for at least 2 years
* No prior 5-azacitidine or decitabine therapy
* No prior treatment for leukemia or myelodysplastic syndrome with four permissible exceptions:

  * Emergency leukapheresis
  * Emergency treatment for hyperleukocytosis with hydroxyurea
  * Cranial radiation therapy (RT) for central nervous system (CNS) leukostasis (one dose only)
  * Growth factor/cytokine support

Primary outcomes:
measure: Number of Participants Who Completed Maintenance Decitabine.
timeFrame: Up to 5 years
measure: Disease-free Survival (DFS) Rate at 1 Year
timeFrame: At 1 year
Secondary outcomes:
Other outcomes:
measure: Relationship Between Busulfan Pharmacokinetics (Area Under the Curve) and Relapsed Disease
timeFrame: At baseline, after 2, 4, and 6 hours after the start of busulfan infusion
Locations:
city: San Francisco
country: United States
facility: UCSF Medical Center-Mount Zion
state: California
city: Lewes
country: United States
facility: Beebe Medical Center
state: Delaware
city: Newark
country: United States
facility: Christiana Care Health System-Christiana Hospital
state: Delaware
city: Orlando
country: United States
facility: Florida Hospital Orlando
state: Florida
city: Atlanta
country: United States
facility: Blood and Marrow Transplant Group of Georgia
state: Georgia
city: Chicago
country: United States
facility: University of Illinois
state: Illinois
city: Chicago
country: United States
facility: University of Chicago Comprehensive Cancer Center
state: Illinois
city: Evanston
country: United States
facility: NorthShore University HealthSystem-Evanston Hospital
state: Illinois
city: Fort Wayne
country: United States
facility: Fort Wayne Medical Oncology and Hematology Inc-Parkview
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa/Holden Comprehensive Cancer Center
state: Iowa
city: Bangor
country: United States
facility: Eastern Maine Medical Center
state: Maine
city: Baltimore
country: United States
facility: University of Maryland/Greenebaum Cancer Center
state: Maryland
city: Bethesda
country: United States
facility: Walter Reed National Military Medical Center
state: Maryland
city: Elkton
country: United States
facility: Union Hospital of Cecil County
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital Cancer Center
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Worcester
country: United States
facility: Commonwealth Hematology Oncology PC-Worcester
state: Massachusetts
city: Columbia
country: United States
facility: Veterans Administration
state: Missouri
city: Columbia
country: United States
facility: University of Missouri - Ellis Fischel
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: North Platte
country: United States
facility: Great Plains Health Callahan Cancer Center
state: Nebraska
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Las Vegas
country: United States
facility: University Medical Center of Southern Nevada
state: Nevada
city: Las Vegas
country: United States
facility: Nevada Cancer Research Foundation CCOP
state: Nevada
city: Las Vegas
country: United States
facility: Sunrise Hospital and Medical Center
state: Nevada
city: Keene
country: United States
facility: Cheshire Medical Center-Dartmouth-Hitchcock Keene
state: New Hampshire
city: Lebanon
country: United States
facility: Dartmouth Hitchcock Medical Center
state: New Hampshire
city: Camden
country: United States
facility: Cooper Hospital University Medical Center
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Lake Success
country: United States
facility: Northwell Health NCORP
state: New York
city: Lake Success
country: United States
facility: Northwell Health/Center for Advanced Medicine
state: New York
city: Manhasset
country: United States
facility: North Shore University Hospital
state: New York
city: New Hyde Park
country: United States
facility: Long Island Jewish Medical Center
state: New York
city: New York
country: United States
facility: Mount Sinai Hospital
state: New York
city: Syracuse
country: United States
facility: State University of New York Upstate Medical University
state: New York
city: Chapel Hill
country: United States
facility: UNC Lineberger Comprehensive Cancer Center
state: North Carolina
city: Goldsboro
country: United States
facility: Wayne Memorial Hospital
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Columbus
country: United States
facility: Ohio State University Comprehensive Cancer Center
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Pittsburgh
country: United States
facility: West Penn Hospital
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Providence
country: United States
facility: Miriam Hospital
state: Rhode Island
city: Berlin
country: United States
facility: Central Vermont Medical Center/National Life Cancer Treatment
state: Vermont
city: Burlington
country: United States
facility: University of Vermont College of Medicine
state: Vermont
Study officials:
affiliation: Alliance for Clinical Trials in Oncology
name: William Blum
role: PRINCIPAL_INVESTIGATOR
References:
citation: Yin J, LaPlant B, Uy GL, Marcucci G, Blum W, Larson RA, Stone RM, Mandrekar SJ. Evaluation of event-free survival as a robust end point in untreated acute myeloid leukemia (Alliance A151614). Blood Adv. 2019 Jun 11;3(11):1714-1721. doi: 10.1182/bloodadvances.2018026112.
citation: Blum W, Sanford BL, Klisovic R, DeAngelo DJ, Uy G, Powell BL, Stock W, Baer MR, Kolitz JE, Wang ES, Hoke E, Mrozek K, Kohlschmidt J, Bloomfield CD, Geyer S, Marcucci G, Stone RM, Larson RA; Alliance for Clinical Trials in Oncology. Maintenance therapy with decitabine in younger adults with acute myeloid leukemia in first remission: a phase 2 Cancer and Leukemia Group B Study (CALGB 10503). Leukemia. 2017 Jan;31(1):34-39. doi: 10.1038/leu.2016.252. Epub 2016 Sep 13.