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

National Cancer Institute (NCI)

Status and phase: Completed; Phase 3

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

Treatments: Drug: cytarabine; Drug: daunorubicin hydrochloride; Other: laboratory biomarker analysis; Biological: oblimersen sodium

Study type: Interventional

Funder types: NIH

Identifiers

NCT00085124

CDR367323

U10CA031946 (U.S. NIH Grant/Contract)

NCI-2012-02805

CALGB-10201

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 500 patients

Sex: All

Ages: 60+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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500 participants in 2 patient groups

Arm I

Experimental group

Description:

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.

Treatment:

Other: laboratory biomarker analysis

Biological: oblimersen sodium

Drug: daunorubicin hydrochloride

Drug: cytarabine

Arm II

Experimental group

Description:

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.

Treatment:

Other: laboratory biomarker analysis

Drug: daunorubicin hydrochloride

Drug: cytarabine