Daunorubicin Hydrochloride, Cytarabine and Oblimersen Sodium in Treating Patients With Previously Untreated Acute Myeloid Leukemia

Study Overview
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Brief Summary
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This randomized phase III trial is studying daunorubicin, cytarabine, and oblimersen to see how well they work compared to daunorubicin and cytarabine in treating older patients with previously untreated acute myeloid leukemia. Drugs used in chemotherapy, such as daunorubicin and cytarabine, work in different ways to stop cancer cells from dividing so they stop growing or die. Oblimersen may increase the effectiveness of daunorubicin and cytarabine by making cancer cells more sensitive to the drugs. It is not yet known whether daunorubicin and cytarabine are more effective with or without oblimersen in treating acute myeloid leukemia.

Detailed Description
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OBJECTIVES: Primary I. Compare outcome, in terms of overall survival, disease-free survival, event-free survival, and complete response rate, in older patients with previously untreated acute myeloid leukemia treated with daunorubicin and cytarabine with or without oblimersen. Secondary I. Determine the significance of expression of select Bcl-2 family member proteins known to be modulated by oblimersen (e.g., Bcl-2) or which potentially mediate resistance to oblimersen (e.g., Bcl-XL or Mcl-1) in predicting clinical outcomes in patients treated with these regimens. II. Correlate clinical outcomes with serial changes in levels of mRNA and protein expression of Bcl-2, its pro-apoptotic binding partner Bax, and other anti-apoptotic Bax-binding proteins (e.g., Bcl-XL or Mcl-1) in patients treated with these regimens. III. Determine the effect of pre-treatment characteristics (e.g., morphology, cytogenetics, molecular features, expression of multidrug resistance molecules, functional assays of drug efflux, prior myelodysplastic syndromes, age, and white blood cells) on toxicity of these regimens and outcomes in these patients. OUTLINE: This is a randomized, multicenter study. Patients are randomized to 1 of 2 treatment arms. Arm I: Remission induction therapy: Patients receive oblimersen IV continuously on days 1-10, cytarabine IV continuously on days 4-10, and daunorubicin IV on days 4-6. Patients who achieve complete remission (CR) proceed to consolidation therapy. Patients who do not achieve CR receive a second course of induction therapy. Second remission induction therapy: Patients receive oblimersen IV continuously on days 1-8, cytarabine IV continuously on days 4-8, and daunorubicin IV on days 4-5. Patients who achieve CR proceed to consolidation therapy. Consolidation therapy: Patients receive oblimersen IV continuously on days 1-8 and high-dose cytarabine IV over 3 hours on days 4-8. Patients with a continuing CR receive a second course of consolidation therapy. Arm II: Remission induction therapy: Patients receive cytarabine IV continuously on days 1-7 and daunorubicin IV on days 1-3. Patients who achieve CR proceed to consolidation therapy. Patients who do not achieve CR receive a second course of induction therapy. Second remission induction therapy: Patients receive cytarabine IV continuously on days 1-5 and daunorubicin IV on days 1 and 2. Patients who achieve CR proceed to consolidation therapy. Consolidation therapy: Patients receive high-dose cytarabine IV over 3 hours on days 1-5. Patients with a continuing CR receive a second course of consolidation therapy. In both arms, treatment continues in the absence of disease progression, unacceptable toxicity, failure to achieve CR after 2 courses of remission induction therapy, the presence of leukemic cells in the cerebrospinal fluid, leukemic regrowth, or relapse during consolidation therapy. Patients are followed every 2 months for 2 years, every 3 months for 2 years, and then annually for 10 years. PROJECTED ACCRUAL: A total of 500 patients (250 per treatment arm) will be accrued for this study within 4.2 years.

Official Title
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A Phase III Study of Daunorubicin and Cytarabine +/- G3139 (Genasense, Oblimersen Sodium, NSC #683428, IND #58842), a BCL2 Antisense Oligodeoxynucleotide, in Previously Untreated Patients With Acute Myeloid Leukemia (AML) &gt; / = 60 Years

Conditions
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Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Inv(16)(p13;q22), Adult Acute Myeloid Leukemia With t(15;17)(q22;q12), Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Acute Myeloid Leukemia With t(8;21)(q22;q22), Secondary Acute Myeloid Leukemia, Untreated Adult Acute Myeloid Leukemia

Intervention / Treatment
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* Biological: oblimersen sodium
* Drug: cytarabine
* Drug: daunorubicin hydrochloride
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: DISEASE CHARACTERISTICS: Histologically confirmed acute myeloid leukemia No promyelocytic leukemia History of antecedent myelodysplasia allowed provided that the patient received no prior cytotoxic therapy for myelodysplastic syndromes PRIOR CONCURRENT THERAPY: Biologic therapy Prior growth factor and/or cytokine support allowed No concurrent routine or prophylactic myeloid growth factors Chemotherapy No prior chemotherapy for leukemia or myelodysplasia except under the following conditions: Emergency leukapheresis Emergency treatment for hyperleukocytosis with hydroxyurea No other concurrent chemotherapy Endocrine therapy No concurrent hormones except steroids for adrenal failure or hormones for non-disease-related conditions allowed (e.g., insulin for diabetes) Radiotherapy Prior cranial radiotherapy for CNS leukostasis (1 dose only) allowed No concurrent palliative radiotherapy Surgery Not specified Other Concurrent enrollment on CALGB-8461, CALGB-9665, and CALGB-9760 allowed No other concurrent investigational or commercial agents or therapies intended to treat the malignancy

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 I<br>Remission induction therapy: Patients receive oblimersen IV continuously on days 1-10, cytarabine IV continuously on days 4-10, and daunorubicin IV on days 4-6. Patients who achieve CR proceed to consolidation therapy. Patients who do not achieve CR receive a second course of induction therapy. Second remission induction therapy: Patients receive oblimersen IV continuously on days 1-8, cytarabine IV continuously on days 4-8, and daunorubicin IV on days 4-5. Patients who achieve CR proceed to consolidation therapy. Consolidation therapy: Patients receive oblimersen IV continuously on days 1-8 and high-dose cytarabine IV over 3 hours on days 4-8. Patients with a continuing CR receive a second course of consolidation therapy. | Biological: oblimersen sodium<br>* Given IV<br>* Other names: Genasense;Drug: cytarabine<br>* Given IV<br>* Other names: cytosine arabinoside;Drug: daunorubicin hydrochloride<br>* Given IV<br>* Other names: RP-13057;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Experimental: Arm II<br>Remission induction therapy: Patients receive cytarabine IV continuously on days 1-7 and daunorubicin IV on days 1-3. Patients who achieve CR proceed to consolidation therapy. Patients who do not achieve CR receive a second course of induction therapy. Second remission induction therapy: Patients receive cytarabine IV continuously on days 1-5 and daunorubicin IV on days 1 and 2. Patients who achieve CR proceed to consolidation therapy. Consolidation therapy: Patients receive high-dose cytarabine IV over 3 hours on days 1-5. Patients with a continuing CR receive a second course of consolidation therapy. | Drug: cytarabine<br>* Given IV<br>* Other names: cytosine arabinoside;Drug: daunorubicin hydrochloride<br>* Given IV<br>* Other names: RP-13057;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) |  | Up to 10 years | 
| Complete response (CR) rate |  | Up to 10 years | 
| Median disease-free survival (DFS) |  | Up to 10 years |