Decitabine With or Without Bortezomib in Treating Older Patients With Acute Myeloid Leukemia

Phase 2

Completed

Conditions: Acute Myeloid Leukemia
Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome
Therapy-Related Acute Myeloid Leukemia

Interventions: Drug: Decitabine
Drug: Bortezomib
Other: Pharmacological Study
Other: Laboratory Biomarker Analysis
Other: Quality-of-Life Assessment
Other: Questionnaire Administration

Registration Number: NCT01420926

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: This randomized phase II trial studies how well giving decitabine with or without bortezomib works in treating older patients with acute myeloid leukemia. Drugs used in chemotherapy, such as decitabine, work in different ways to stop the growth of cancer cells, either by killing the cells,by stopping them from dividing, or by stopping them from spreading. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. It is not yet known whether decitabine works better when given with or without bortezomib in treating acute myeloid leukemia.

Detailed Description: PRIMARY OBJECTIVE:

I. To determine if treatment of older acute myeloid leukemia (AML) patients with decitabine and bortezomib significantly improves the overall survival times of older AML patients compared with decitabine alone.

SECONDARY OBJECTIVES:

I. To determine the rate of complete remission (CR and CR + incomplete blood count recovery \[CRi\]) for each of the 2 treatment regimens in the proposal.

II. To determine the overall survival, progression-free survival, disease-free survival and for each of the treatment regimens on this study.

III. To determine whether ongoing treatment with these regimens prolongs overall survival even in the absence of complete remission.

IV. To describe the frequency and severity of adverse events, as well as the tolerability of each of these regimens in patients treated on this study.

V. To describe the interaction of pretreatment disease and patient characteristics including morphology, cytogenetics, molecular genetics, white blood cell (WBC) count, blood and bone marrow blast count, age, performance status and comprehensive geriatric assessment on clinical outcomes.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: REMISSION INDUCTION THERAPY: Patients receive decitabine intravenously (IV) over 1 hour once daily (QD) on days 1-10. Treatment repeats every 28 days for 2-4 courses in the absence of disease progression or unacceptable toxicity. Patients not achieving CR or CR with CRi proceed to continuation therapy. Patients achieving CR or CR with CRi proceed to maintenance therapy.

CONTINUATION THERAPY: Patients receive decitabine IV over 1 hour QD on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Patients receive decitabine IV over 1 hour QD on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM B: REMISSION INDUCTION THERAPY: Patients receive decitabine IV over 1 hour QD on days 2-11 and bortezomib subcutaneously (SC) on days 1, 4, 8, and 11. Treatment repeats every 28 days for 2-4 courses in the absence of disease progression or unacceptable toxicity. Patients not achieving CR or CRi proceed to continuation therapy. Patients achieving CR or CR with CRi proceed to maintenance therapy.

CONTINUATION THERAPY: Patients receive bortezomib SC on day 1 and decitabine IV over 1 hour QD on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Patients receive bortezomib SC on day 1 and decitabine IV over 1 hour QD on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 2 months for 2 years, every 3 months for 2 years, and then once a year for a maximum of 10 years from study entry.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 165

Inclusion Criteria

Unequivocal pathologic diagnosis of AML (>= 20% blasts in the bone marrow based on World Health Organization [WHO] criteria) EXCLUDING:
- Acute promyelocytic leukemia t(15;17)(q22;q12); PML-RARA
- Acute myeloid leukemia with t(8;21)(q22;q22); RUNX1-RUNXT1 as determined by the Ohio State University (OSU) Molecular Reference Laboratory, per Cancer and Leukemia Group B (CALGB) 20202; however patients who (1) are >= 75 years; and/or (2) have an ejection fraction of < 40%; and/or (3) have a performance status of > 2, may be registered to CALGB 20202 and registered and treated on CALGB 11002 prior to receiving the FLT3 mutation and core-binding factor (CBF) molecular screening results from CALGB 20202
- Acute myeloid leukemia with inv(16)(p13.1;q22) or t(16;16)(p13.1;q22); CBFB-MYH11 as determined by the OSU Molecular Reference Laboratory, per CALGB 20202; however patients who (1) are >= 75 years; and/or (2) have an ejection fraction of < 40%; and/or (3) have a performance status of > 2, may be registered to CALGB 20202 and registered and treated on CALGB 11002 prior to receiving the FLT3 mutation and CBF molecular screening results from CALGB 20202
Absence of FLT3 mutation (ITD or point mutation) determined by the OSU Molecular Reference Laboratory, per CALGB 20202; however patients who (1) are >= 75 years; and/or (2) have an ejection fraction of < 40%; and/or (3) have a performance status of > 2, may be registered to CALGB 20202 and registered and treated on CALGB 11002 prior to receiving the FLT3 mutation and CBF molecular screening results from CALGB 20202
No prior treatment for AML except:
- Emergency leukapheresis
- Emergency treatment for hyperleukocytosis with hydroxyurea
- Cranial radiotherapy (RT) for central nervous system (CNS) leukostasis (one dose only)
- Growth factor/cytokine support
AML patients with an antecedent hematologic disorder (AHD) or myelodysplastic syndrome (MDS) are eligible for this trial provided that they have not received treatment for their AHD or MDS with cytotoxic chemotherapy (e.g., cytarabine, daunorubicin, etc.), decitabine, or bortezomib; patients may have been previously treated with azacitidine if their last dose was >= 90 days prior to starting 11002
AML patients with therapy-related myeloid neoplasms (t-MN) are eligible if they have not received radiation therapy or chemotherapy (not including hormonal therapy) for their primary malignancy or disorder for > 6 months

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm A (decitabine)	Pharmacological Study	REMISSION INDUCTION THERAPY: Patients receive 20 mg/m\^2 decitabine IV over 1 hour QD on days 1-10. Treatment repeats every 28 days for 2-4 courses in the absence of disease progression or unacceptable toxicity. Patients not achieving CR CRi proceed to continuation therapy. Patients achieving CR or CRi proceed to maintenance therapy. CONTINUATION THERAPY: Patients receive 20 mg/m\^2 decitabine IV over 1 hour QD on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive 20 mg/m\^2 decitabine IV over 1 hour QD on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Arm A (decitabine)	Questionnaire Administration	REMISSION INDUCTION THERAPY: Patients receive 20 mg/m\^2 decitabine IV over 1 hour QD on days 1-10. Treatment repeats every 28 days for 2-4 courses in the absence of disease progression or unacceptable toxicity. Patients not achieving CR CRi proceed to continuation therapy. Patients achieving CR or CRi proceed to maintenance therapy. CONTINUATION THERAPY: Patients receive 20 mg/m\^2 decitabine IV over 1 hour QD on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive 20 mg/m\^2 decitabine IV over 1 hour QD on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Arm B (decitabine and bortezomib)	Laboratory Biomarker Analysis	REMISSION INDUCTION THERAPY: Patients receive 20 mg/m\^2 decitabine IV over 1 hour QD on days 2-11 and 1.3 mg/m\^2 bortezomib SC on days 1, 4, 8, and 11. Treatment repeats every 28 days for 2-4 courses in the absence of disease progression or unacceptable toxicity. Patients not achieving CR or CRi proceed to continuation therapy. Patients achieving CR or CRi proceed to maintenance therapy. CONTINUATION THERAPY: Patients receive 1.3 mg/m\^2 bortezomib SC on day 1 and 20 mg/m\^2 decitabine IV over 1 hour QD on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive 1.3 mg/m\^2 bortezomib SC on day 1 and 20 mg/m\^2 decitabine IV over 1 hour QD on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Arm A (decitabine)	Laboratory Biomarker Analysis	REMISSION INDUCTION THERAPY: Patients receive 20 mg/m\^2 decitabine IV over 1 hour QD on days 1-10. Treatment repeats every 28 days for 2-4 courses in the absence of disease progression or unacceptable toxicity. Patients not achieving CR CRi proceed to continuation therapy. Patients achieving CR or CRi proceed to maintenance therapy. CONTINUATION THERAPY: Patients receive 20 mg/m\^2 decitabine IV over 1 hour QD on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive 20 mg/m\^2 decitabine IV over 1 hour QD on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Arm A (decitabine)	Quality-of-Life Assessment	REMISSION INDUCTION THERAPY: Patients receive 20 mg/m\^2 decitabine IV over 1 hour QD on days 1-10. Treatment repeats every 28 days for 2-4 courses in the absence of disease progression or unacceptable toxicity. Patients not achieving CR CRi proceed to continuation therapy. Patients achieving CR or CRi proceed to maintenance therapy. CONTINUATION THERAPY: Patients receive 20 mg/m\^2 decitabine IV over 1 hour QD on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive 20 mg/m\^2 decitabine IV over 1 hour QD on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Arm B (decitabine and bortezomib)	Pharmacological Study	REMISSION INDUCTION THERAPY: Patients receive 20 mg/m\^2 decitabine IV over 1 hour QD on days 2-11 and 1.3 mg/m\^2 bortezomib SC on days 1, 4, 8, and 11. Treatment repeats every 28 days for 2-4 courses in the absence of disease progression or unacceptable toxicity. Patients not achieving CR or CRi proceed to continuation therapy. Patients achieving CR or CRi proceed to maintenance therapy. CONTINUATION THERAPY: Patients receive 1.3 mg/m\^2 bortezomib SC on day 1 and 20 mg/m\^2 decitabine IV over 1 hour QD on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive 1.3 mg/m\^2 bortezomib SC on day 1 and 20 mg/m\^2 decitabine IV over 1 hour QD on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Arm B (decitabine and bortezomib)	Quality-of-Life Assessment	REMISSION INDUCTION THERAPY: Patients receive 20 mg/m\^2 decitabine IV over 1 hour QD on days 2-11 and 1.3 mg/m\^2 bortezomib SC on days 1, 4, 8, and 11. Treatment repeats every 28 days for 2-4 courses in the absence of disease progression or unacceptable toxicity. Patients not achieving CR or CRi proceed to continuation therapy. Patients achieving CR or CRi proceed to maintenance therapy. CONTINUATION THERAPY: Patients receive 1.3 mg/m\^2 bortezomib SC on day 1 and 20 mg/m\^2 decitabine IV over 1 hour QD on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive 1.3 mg/m\^2 bortezomib SC on day 1 and 20 mg/m\^2 decitabine IV over 1 hour QD on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Arm B (decitabine and bortezomib)	Questionnaire Administration	REMISSION INDUCTION THERAPY: Patients receive 20 mg/m\^2 decitabine IV over 1 hour QD on days 2-11 and 1.3 mg/m\^2 bortezomib SC on days 1, 4, 8, and 11. Treatment repeats every 28 days for 2-4 courses in the absence of disease progression or unacceptable toxicity. Patients not achieving CR or CRi proceed to continuation therapy. Patients achieving CR or CRi proceed to maintenance therapy. CONTINUATION THERAPY: Patients receive 1.3 mg/m\^2 bortezomib SC on day 1 and 20 mg/m\^2 decitabine IV over 1 hour QD on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive 1.3 mg/m\^2 bortezomib SC on day 1 and 20 mg/m\^2 decitabine IV over 1 hour QD on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Arm A (decitabine)	Decitabine	REMISSION INDUCTION THERAPY: Patients receive 20 mg/m\^2 decitabine IV over 1 hour QD on days 1-10. Treatment repeats every 28 days for 2-4 courses in the absence of disease progression or unacceptable toxicity. Patients not achieving CR CRi proceed to continuation therapy. Patients achieving CR or CRi proceed to maintenance therapy. CONTINUATION THERAPY: Patients receive 20 mg/m\^2 decitabine IV over 1 hour QD on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive 20 mg/m\^2 decitabine IV over 1 hour QD on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Arm B (decitabine and bortezomib)	Decitabine	REMISSION INDUCTION THERAPY: Patients receive 20 mg/m\^2 decitabine IV over 1 hour QD on days 2-11 and 1.3 mg/m\^2 bortezomib SC on days 1, 4, 8, and 11. Treatment repeats every 28 days for 2-4 courses in the absence of disease progression or unacceptable toxicity. Patients not achieving CR or CRi proceed to continuation therapy. Patients achieving CR or CRi proceed to maintenance therapy. CONTINUATION THERAPY: Patients receive 1.3 mg/m\^2 bortezomib SC on day 1 and 20 mg/m\^2 decitabine IV over 1 hour QD on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive 1.3 mg/m\^2 bortezomib SC on day 1 and 20 mg/m\^2 decitabine IV over 1 hour QD on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Arm B (decitabine and bortezomib)	Bortezomib	REMISSION INDUCTION THERAPY: Patients receive 20 mg/m\^2 decitabine IV over 1 hour QD on days 2-11 and 1.3 mg/m\^2 bortezomib SC on days 1, 4, 8, and 11. Treatment repeats every 28 days for 2-4 courses in the absence of disease progression or unacceptable toxicity. Patients not achieving CR or CRi proceed to continuation therapy. Patients achieving CR or CRi proceed to maintenance therapy. CONTINUATION THERAPY: Patients receive 1.3 mg/m\^2 bortezomib SC on day 1 and 20 mg/m\^2 decitabine IV over 1 hour QD on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive 1.3 mg/m\^2 bortezomib SC on day 1 and 20 mg/m\^2 decitabine IV over 1 hour QD on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Overall Survival (OS) Time	48 months	Overall survival (OS) was defined as the time from study entry to death of any cause. Surviving patients were censored at the date of last follow-up. The median OS with 95% CI was estimated using the Kaplan Meier method.

Secondary Outcome Measures

Name	Time	Method
Progression-free Survival	48 months	Progression free survival (PFS) was defined as the time from study entry to progression or death. Progression free and surviving patients were censored at the date of last follow-up. The median DFS with 95% CI was estimated using the Kaplan Meier method.
Adverse Events	48 months	Adverse Events: Incidence of adverse events, assessed using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Adverse events were collected every cycle during treatment and up to one month after treatment. Adverse events were summarized using summary statistics and frequency tables for each separate cohort. Per protocol, analysis was descriptive in nature. In this section, the number of patients that reported a grade 4 or higher event are summarized. A complete listing of Adverse Events is provided in the Adverse Events section below.
Complete Remission Rate (CR and CRi)	48 months	Defined as the number of patients who achieve a CR or CRi divided by the total number of evaluable patients. A Complete remission (CR) requires: \<5% marrow blast, \> 200 nucleated cells, no blasts with auer rods, no extramedullary disease, ANC \>1,000/mm\^3 and platelets \> 100,000/mm\^3. A CR with incomplete blood count recovery (CRi) is defined as CR with exception of ANC \< 1,000/mm\^3 or platelets \< 100,000/mm\^3.
Disease-free Survival (DFS)	48 months	Disease free survival (DFS) was defined as the time from CR to relapse or death. Relapse free and surviving patients were censored at the date of last follow-up. The median DFS with 95% CI was estimated using the Kaplan Meier method. Relapse is defined as the reappearance of blood blasts or \>= 5% marrow blasts after achieving a CR or CRi.

Trial Locations

Locations (53): NorthShore University HealthSystem-Evanston Hospital
🇺🇸
Evanston, Illinois, United States
East Carolina University
🇺🇸
Greenville, North Carolina, United States
Ohio State University Comprehensive Cancer Center
🇺🇸
Columbus, Ohio, United States
Cancer Care Associates-Norman
🇺🇸
Norman, Oklahoma, United States
Massachusetts General Hospital Cancer Center
🇺🇸
Boston, Massachusetts, United States
Christiana Care Health System-Christiana Hospital
🇺🇸
Newark, Delaware, United States
Beebe Medical Center
🇺🇸
Lewes, Delaware, United States
Palo Alto Medical Foundation-Camino Division
🇺🇸
Mountain View, California, United States
University of Chicago Comprehensive Cancer Center
🇺🇸
Chicago, Illinois, United States
Hartford Hospital
🇺🇸
Hartford, Connecticut, United States
Fort Wayne Medical Oncology and Hematology Inc-Parkview
🇺🇸
Fort Wayne, Indiana, United States
Mercy Health Saint Mary's
🇺🇸
Grand Rapids, Michigan, United States
University of Iowa/Holden Comprehensive Cancer Center
🇺🇸
Iowa City, Iowa, United States
Christiana Care - Union Hospital
🇺🇸
Elkton, Maryland, United States
Harold Alfond Center for Cancer Care
🇺🇸
Augusta, Maine, United States
Eastern Maine Medical Center
🇺🇸
Bangor, Maine, United States
Dana-Farber Cancer Institute
🇺🇸
Boston, Massachusetts, United States
Bronson Battle Creek
🇺🇸
Battle Creek, Michigan, United States
Cancer Research Consortium of West Michigan NCORP
🇺🇸
Grand Rapids, Michigan, United States
Spectrum Health Big Rapids Hospital
🇺🇸
Big Rapids, Michigan, United States
Novant Health Presbyterian Medical Center
🇺🇸
Charlotte, North Carolina, United States
Spectrum Health at Butterworth Campus
🇺🇸
Grand Rapids, Michigan, United States
Wayne Memorial Hospital
🇺🇸
Goldsboro, North Carolina, United States
Northwell Health/Center for Advanced Medicine
🇺🇸
Lake Success, New York, United States
Dartmouth Hitchcock Medical Center
🇺🇸
Lebanon, New Hampshire, United States
Cooper Hospital University Medical Center
🇺🇸
Camden, New Jersey, United States
University of Missouri - Ellis Fischel
🇺🇸
Columbia, Missouri, United States
NYP/Weill Cornell Medical Center
🇺🇸
New York, New York, United States
Roswell Park Cancer Institute
🇺🇸
Buffalo, New York, United States
Central Vermont Medical Center/National Life Cancer Treatment
🇺🇸
Berlin, Vermont, United States
Munson Medical Center
🇺🇸
Traverse City, Michigan, United States
Brigham and Women's Hospital
🇺🇸
Boston, Massachusetts, United States
Spectrum Health Reed City Hospital
🇺🇸
Reed City, Michigan, United States
Mercy Health Mercy Campus
🇺🇸
Muskegon, Michigan, United States
Vidant Oncology-Kinston
🇺🇸
Kinston, North Carolina, United States
North Shore University Hospital
🇺🇸
Manhasset, New York, United States
Northwell Health NCORP
🇺🇸
Lake Success, New York, United States
Long Island Jewish Medical Center
🇺🇸
New Hyde Park, New York, United States
Mount Sinai Hospital
🇺🇸
New York, New York, United States
Margaret R Pardee Memorial Hospital
🇺🇸
Hendersonville, North Carolina, United States
Prisma Health Cancer Institute - Spartanburg
🇺🇸
Boiling Springs, South Carolina, United States
Prisma Health Cancer Institute - Butternut
🇺🇸
Greenville, South Carolina, United States
Prisma Health Cancer Institute - Faris
🇺🇸
Greenville, South Carolina, United States
Prisma Health Cancer Institute - Greer
🇺🇸
Greer, South Carolina, United States
Prisma Health Cancer Institute - Eastside
🇺🇸
Greenville, South Carolina, United States
University of Vermont and State Agricultural College
🇺🇸
Burlington, Vermont, United States
Mercy Hospital Oklahoma City
🇺🇸
Oklahoma City, Oklahoma, United States
AdventHealth Orlando
🇺🇸
Orlando, Florida, United States
UNC Lineberger Comprehensive Cancer Center
🇺🇸
Chapel Hill, North Carolina, United States
MedStar Georgetown University Hospital
🇺🇸
Washington, District of Columbia, United States
Wake Forest University Health Sciences
🇺🇸
Winston-Salem, North Carolina, United States
Prisma Health Greenville Memorial Hospital
🇺🇸
Greenville, South Carolina, United States
Prisma Health Cancer Institute - Seneca
🇺🇸
Seneca, South Carolina, United States