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

Study Overview
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Brief Summary
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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
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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.

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

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

Intervention / Treatment
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* Drug: Bortezomib
* Drug: Decitabine
* Other: Laboratory Biomarker Analysis
* Other: Pharmacological Study
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (decitabine)<br>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. | Drug: Decitabine<br>* Given IV<br>* Other names: Dezocitidine;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Experimental: Arm B (decitabine and bortezomib)<br>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. | Drug: Bortezomib<br>* Given SC<br>* Other names: Velcade;Drug: Decitabine<br>* Given IV<br>* Other names: Dezocitidine;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|

What is the study measuring?
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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 |