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

A Randomized Phase II Trial of Decitabine-Based Induction Strategies for Patients >/= 60 Years Old With Acute Myeloid Leukemia (AML)

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.

Study Overview

• Status: Completed
• Conditions: Acute Myeloid Leukemia; Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Therapy-Related Acute Myeloid Leukemia
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Other: Quality-of-Life Assessment; Drug: Decitabine; Other: Pharmacological Study; Other: Questionnaire Administration; Drug: Bortezomib

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.

• Study Type: Interventional
• Enrollment (Actual): 165
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Mountain View, California, United States, 94040
      • Palo Alto Medical Foundation-Camino Division
  • Connecticut
    • Hartford, Connecticut, United States, 06102
      • Hartford Hospital
  • Delaware
    • Lewes, Delaware, United States, 19958
      • Beebe Medical Center
    • Newark, Delaware, United States, 19718
      • Christiana Care Health System-Christiana Hospital
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • MedStar Georgetown University Hospital
  • Florida
    • Orlando, Florida, United States, 32803
      • AdventHealth Orlando
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Comprehensive Cancer Center
    • Evanston, Illinois, United States, 60201
      • NorthShore University HealthSystem-Evanston Hospital
  • Indiana
    • Fort Wayne, Indiana, United States, 46845
      • Fort Wayne Medical Oncology and Hematology Inc-Parkview
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa/Holden Comprehensive Cancer Center
  • Maine
    • Augusta, Maine, United States, 04330
      • Harold Alfond Center for Cancer Care
    • Bangor, Maine, United States, 04401
      • Eastern Maine Medical Center
  • Maryland
    • Elkton, Maryland, United States, 21921
      • Christiana Care - Union Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Cancer Center
  • Michigan
    • Battle Creek, Michigan, United States, 49017
      • Bronson Battle Creek
    • Big Rapids, Michigan, United States, 49307
      • Spectrum Health Big Rapids Hospital
    • Grand Rapids, Michigan, United States, 49503
      • Spectrum Health at Butterworth Campus
    • Grand Rapids, Michigan, United States, 49503
      • Mercy Health Saint Mary's
    • Grand Rapids, Michigan, United States, 49503
      • Cancer Research Consortium of West Michigan NCORP
    • Muskegon, Michigan, United States, 49444
      • Mercy Health Mercy Campus
    • Reed City, Michigan, United States, 49677
      • Spectrum Health Reed City Hospital
    • Traverse City, Michigan, United States, 49684
      • Munson Medical Center
  • Missouri
    • Columbia, Missouri, United States, 65212
      • University of Missouri - Ellis Fischel
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth Hitchcock Medical Center
  • New Jersey
    • Camden, New Jersey, United States, 08103
      • Cooper Hospital University Medical Center
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
    • Lake Success, New York, United States, 11042
      • Northwell Health NCORP
    • Lake Success, New York, United States, 11042
      • Northwell Health/Center for Advanced Medicine
    • Manhasset, New York, United States, 11030
      • North Shore University Hospital
    • New Hyde Park, New York, United States, 11040
      • Long Island Jewish Medical Center
    • New York, New York, United States, 10029
      • Mount Sinai Hospital
    • New York, New York, United States, 10065
      • NYP/Weill Cornell Medical Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • UNC Lineberger Comprehensive Cancer Center
    • Charlotte, North Carolina, United States, 28204
      • Novant Health Presbyterian Medical Center
    • Goldsboro, North Carolina, United States, 27534
      • Wayne Memorial Hospital
    • Greenville, North Carolina, United States, 27834
      • East Carolina University
    • Hendersonville, North Carolina, United States, 28791
      • Margaret R Pardee Memorial Hospital
    • Kinston, North Carolina, United States, 28501
      • Vidant Oncology-Kinston
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Health Sciences
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University Comprehensive Cancer Center
  • Oklahoma
    • Norman, Oklahoma, United States, 73071
      • Cancer Care Associates-Norman
    • Oklahoma City, Oklahoma, United States, 73120
      • Mercy Hospital Oklahoma City
  • South Carolina
    • Boiling Springs, South Carolina, United States, 29316
      • Prisma Health Cancer Institute - Spartanburg
    • Greenville, South Carolina, United States, 29605
      • Prisma Health Cancer Institute - Faris
    • Greenville, South Carolina, United States, 29615
      • Prisma Health Cancer Institute - Eastside
    • Greenville, South Carolina, United States, 29605
      • Prisma Health Cancer Institute - Butternut
    • Greenville, South Carolina, United States, 29605
      • Prisma Health Greenville Memorial Hospital
    • Greer, South Carolina, United States, 29650
      • Prisma Health Cancer Institute - Greer
    • Seneca, South Carolina, United States, 29672
      • Prisma Health Cancer Institute - Seneca
  • Vermont
    • Berlin, Vermont, United States, 05602
      • Central Vermont Medical Center/National Life Cancer Treatment
    • Burlington, Vermont, United States, 05405
      • University of Vermont and State Agricultural College

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A (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.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Quality-of-Life Assessment; Ancillary studies; Other Names: Quality of Life Assessment; Drug: Decitabine; Given IV; Other Names: 5-Aza-2'-deoxycytidine; Dacogen; Decitabine for Injection; Deoxyazacytidine; Dezocitidine; Other: Pharmacological Study; Correlative studies; Other: Questionnaire Administration; Ancillary studies
Experimental: Arm B (decitabine and 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.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Quality-of-Life Assessment; Ancillary studies; Other Names: Quality of Life Assessment; Drug: Decitabine; Given IV; Other Names: 5-Aza-2'-deoxycytidine; Dacogen; Decitabine for Injection; Deoxyazacytidine; Dezocitidine; Other: Pharmacological Study; Correlative studies; Other: Questionnaire Administration; Ancillary studies; Drug: Bortezomib; Given SC; Other Names: Velcade; MLN341; PS-341; LDP 341; [(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic Acid; PS341

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS) Time	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.	48 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Remission Rate (CR and CRi)	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.	48 months
Disease-free Survival (DFS)	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.	48 months
Progression-free Survival	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.	48 months
Adverse Events	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.	48 months

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Gail J Roboz, Alliance for Clinical Trials in Oncology

Publications and helpful links

General Publications

• Ritchie EK, Klepin HD, Storrick E, Major B, Le-Rademacher J, Wadleigh M, Walker A, Larson RA, Roboz GJ. Geriatric assessment for older adults receiving less-intensive therapy for acute myeloid leukemia: report of CALGB 361101. Blood Adv. 2022 Jun 28;6(12):3812-3820. doi: 10.1182/bloodadvances.2021006872.
• Roboz GJ, Mandrekar SJ, Desai P, Laumann K, Walker AR, Wang ES, Kolitz JE, Powell BL, Attar EC, Stock W, Bloomfield CD, Kohlschmidt J, Mrozek K, Hassane DC, Garraway L, Jane-Valbuena J, Baltay M, Tracy A, Marcucci G, Stone RM, Larson RA. Randomized trial of 10 days of decitabine +/- bortezomib in untreated older patients with AML: CALGB 11002 (Alliance). Blood Adv. 2018 Dec 26;2(24):3608-3617. doi: 10.1182/bloodadvances.2018023689.

Study record dates

Study Major Dates

• Study Start (Actual): November 16, 2011
• Primary Completion (Actual): June 5, 2016
• Study Completion (Actual): April 1, 2021

Study Registration Dates

• First Submitted: August 19, 2011
• First Submitted That Met QC Criteria: August 19, 2011
• First Posted (Estimate): August 22, 2011

Study Record Updates

• Last Update Posted (Estimate): February 28, 2023
• Last Update Submitted That Met QC Criteria: February 2, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Decitabine; Bortezomib
• Other Study ID Numbers: NCI-2011-02987 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); U10CA180821 (U.S. NIH Grant/Contract); U10CA031946 (U.S. NIH Grant/Contract); CDR0000709218; CALGB-11002 (Other Identifier: CTEP)