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

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Completed

CT.gov ID

NCT00039117

Collaborator

(none)

Enrollment

Location

Arm

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
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	Biological: oblimersen sodium Drug: cytarabine Drug: daunorubicin hydrochloride Other: laboratory biomarker analysis Other: pharmacological study	Phase 1

Detailed Description

OBJECTIVES:

Determine the maximum tolerated dose of daunorubicin in combination with cytarabine and oblimersen in older patients with previously untreated acute myeloid leukemia.
Determine the qualitative and quantitative toxic effects of this regimen in these patients.
Determine the pharmacokinetics of oblimersen in this regimen in these patients.
Determine the disease-free survival and overall survival of patients treated with this regimen.
Assess the spontaneous rate of apoptosis in leukemic blasts in patients before and after initiation of treatment with oblimersen.
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.

Study Design

Study Type:

Interventional

Actual Enrollment :

32 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Apr 1, 2002

Actual Primary Completion Date :

Sep 1, 2003

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I 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 Given IV Other Names: augmerosen G3139 G3139 bcl-2 antisense oligodeoxynucleotide Genasense Drug: cytarabine Given IV Other Names: ARA-C arabinofuranosylcytosine arabinosylcytosine Cytosar-U cytosine arabinoside Drug: daunorubicin hydrochloride Given IV Other Names: Cerubidin Cerubidine daunomycin hydrochloride daunorubicin RP-13057 Other: laboratory biomarker analysis Correlative studies Other: pharmacological study Correlative studies Other Names: pharmacological studies

Arm

Intervention/Treatment

Experimental: Arm I

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

Given IV

Other Names:

augmerosen

G3139

G3139 bcl-2 antisense oligodeoxynucleotide

Genasense

Drug: cytarabine

Given IV

Other Names:

ARA-C

arabinofuranosylcytosine

arabinosylcytosine

Cytosar-U

cytosine arabinoside

Drug: daunorubicin hydrochloride

Given IV

Other Names:

Cerubidin

Cerubidine

daunomycin hydrochloride

daunorubicin

RP-13057

Other: laboratory biomarker analysis

Correlative studies

Other: pharmacological study

Correlative studies

Other Names:

pharmacological studies

Outcome Measures

Primary Outcome Measures

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 [Up to 2 years]
We will define the qualitative and quantitative toxicities in regard to organ specificity, time course, predictability, and reversibility.

Secondary Outcome Measures

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

60 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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