Oblimersen, Cytarabine, and Daunorubicin in Treating Older Patients With Acute Myeloid Leukemia

Study Overview
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Brief Summary
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Phase I trial to study the effectiveness of combining oblimersen with cytarabine and daunorubicin in treating older patients who have previously untreated acute myeloid leukemia. Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Oblimersen may help cytarabine and daunorubicin kill more cancer cells by making them more sensitive to chemotherapy.

Detailed Description
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OBJECTIVES: I. Determine the maximum tolerated dose of daunorubicin in combination with cytarabine and oblimersen in older patients with previously untreated acute myeloid leukemia. II. Determine the qualitative and quantitative toxic effects of this regimen in these patients. III. Determine the pharmacokinetics of oblimersen in this regimen in these patients. IV. Determine the disease-free survival and overall survival of patients treated with this regimen. V. Assess the spontaneous rate of apoptosis in leukemic blasts in patients before and after initiation of treatment with oblimersen. VI. Determine therapeutic response (complete remission) in patients treated with this regimen. OUTLINE: This is a dose-escalation study of daunorubicin. Patients are stratified according to disease status (primary vs secondary). INDUCTION THERAPY: Patients receive oblimersen (G3139) IV continuously on days 1-10 and cytarabine IV continuously on days 4-10. Patients also receive daunorubicin IV daily on days 4-6. Patients with bone marrow cellularity of at least 20% and at least 5% leukemic blasts at day 17 or evidence of refractory disease receive a second induction comprising G3139 IV continuously on days 1-8, cytarabine IV continuously on days 4-8, and daunorubicin IV on days 4-5. CONSOLIDATION THERAPY: Beginning no sooner than 14 days after hematologic recovery from induction therapy, patients receive G3139 IV continuously on days 1-8 and cytarabine IV over 4 hours on days 4-8. Patients receive a second course of consolidation therapy no sooner than 14 days after hematologic recovery from the first course. Cohorts of 3-6 patients receive escalating doses of daunorubicin until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Patients are followed every 2 months for 2 years.

Official Title
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A Phase I Study of G3139 ( NSC # 683428) in Combination With Cytarabine and Daunorubicin in Previously Untreated Patients With Acute Myeloid Leukemia (AML)&gt;= 60 Years of Age

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(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
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed primary or secondary acute myeloid leukemia (AML) More than 20% bone marrow blasts Myelodysplastic syndromes (MDS) or a chronic myeloproliferative disorder antecedent to AML allowed Therapy-related AML allowed No acute promyelocytic leukemia At least 4 weeks Bilirubin no greater than 2 mg/dL ALT and AST no greater than 2 times upper limit of normal (unless directly attributable to AML) Creatinine no greater than 2.5 mg/dL Ejection fraction at least 50% by MUGA or echocardiogram No symptomatic congestive heart failure No unstable angina pectoris No cardiac arrhythmia No allergy to any of the study medications No other uncontrolled concurrent illness No serious medical or psychiatric illness that would preclude giving informed consent Not pregnant or nursing Fertile patients must use effective contraception No prior therapy for primary AML except emergency leukapheresis No prior anthracyclines No prior chemotherapy for primary AML except hydroxyurea for hyperleukocytosis At least 3 months since prior chemotherapy for MDS or chronic myeloproliferative disorders antecedent to AML No other concurrent chemotherapy No concurrent corticosteroids as anti-emetics No concurrent steroids except for adrenal failure or septic shock No concurrent hormonal therapy except hormones for non-disease-related conditions (e.g., insulin for diabetes, tamoxifen or equivalent for breast cancer prevention or adjuvant treatment, or estrogens or progestins for gynecologic indications) No prior radiotherapy for primary AML except cranial radiotherapy for CNS leukostasis No concurrent palliative radiotherapy No concurrent whole brain radiotherapy No other concurrent investigational or commercial agents or therapies No concurrent cyclooxygenase-2 inhibitors

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>INDUCTION THERAPY: Patients receive oblimersen (G3139) IV continuously on days 1-10 and cytarabine IV continuously on days 4-10. Patients also receive daunorubicin IV daily on days 4-6. Patients with bone marrow cellularity of at least 20% and at least 5% leukemic blasts at day 17 or evidence of refractory disease receive a second induction comprising G3139 IV continuously on days 1-8, cytarabine IV continuously on days 4-8, and daunorubicin IV on days 4-5. CONSOLIDATION THERAPY: Beginning no sooner than 14 days after hematologic recovery from induction therapy, patients receive G3139 IV continuously on days 1-8 and cytarabine IV over 4 hours on days 4-8. Patients receive a second course of consolidation therapy no sooner than 14 days after hematologic recovery from the first course. | 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>Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MTD of cytarabine and daunorubicin in combination with G3139, defined as the dose level just below the dose level at which DLT is observed in 2 patients, graded according to NCI CTC version 2.0 |  | Up to day 10 | 
| Incidence of adverse events, graded according to NCI CTC version 2.0 | We will define the qualitative and quantitative toxicities in regard to organ specificity, time course, predictability, and reversibility. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics of G3139 |  | During induction therapy on day 1 at hour 0 and 24hours after G3139 administration; day 4 at hour 73 before cytarabine administration; day 11 at hour 0 and .5, 1, 2, 4, 6, and 8 hours | 
| Level of bcl-2 in circulating and/or marrow leukemic blasts before and after initiation of treatment with G3139 |  | Up to 18 weeks | 
| Spontaneous rate of apoptosis in leukemic blasts before and after initiation of treatment with G3139 |  | Up to 18 weeks | 
| Incidence of therapeutic response (complete remission [CR]) |  | Up to 2 years | 
| Disease-free survival |  | Up to 2 years | 
| Overall survival |  | Up to 2 years |