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

• ClinicalTrials.gov Identifier: NCT00085124
• Recruitment Status: Completed
• First Posted: June 11, 2004
• Last Update Posted: June 5, 2013
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Study Description

Brief Summary:

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.

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(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	Biological: oblimersen sodium; Drug: cytarabine; Drug: daunorubicin hydrochloride; Other: laboratory biomarker analysis	Phase 3

Detailed 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 500 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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) > / = 60 Years
• Study Start Date: December 2003
• Actual Primary Completion Date: June 2007

Arms and Interventions

Arm	Intervention/treatment
Experimental: 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 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; 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
Experimental: 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.	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

Outcome Measures

Primary Outcome Measures :

1. Overall survival (OS) [ Time Frame: Up to 10 years ]
2. Complete response (CR) rate [ Time Frame: Up to 10 years ]
3. Median disease-free survival (DFS) [ Time Frame: Up to 10 years ]

Eligibility Criteria

• Ages Eligible for Study: 60 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, Illinois

Cancer and Leukemia Group B

Chicago, Illinois, United States, 60606

United States, Ohio

Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center

Columbus, Ohio, United States, 43210

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Guido Marcucci; Cancer and Leukemia Group B

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Walker CJ, Kohlschmidt J, Eisfeld AK, Mrózek K, Liyanarachchi S, Song C, Nicolet D, Blachly JS, Bill M, Papaioannou D, Oakes CC, Giacopelli B, Genutis LK, Maharry SE, Orwick S, Archer KJ, Powell BL, Kolitz JE, Uy GL, Wang ES, Carroll AJ, Stone RM, Byrd JC, de la Chapelle A, Bloomfield CD. Genetic Characterization and Prognostic Relevance of Acquired Uniparental Disomies in Cytogenetically Normal Acute Myeloid Leukemia. Clin Cancer Res. 2019 Nov 1;25(21):6524-6531. doi: 10.1158/1078-0432.CCR-19-0725. Epub 2019 Aug 2.

Yin J, LaPlant B, Uy GL, Marcucci G, Blum W, Larson RA, Stone RM, Mandrekar SJ. Evaluation of event-free survival as a robust end point in untreated acute myeloid leukemia (Alliance A151614). Blood Adv. 2019 Jun 11;3(11):1714-1721. doi: 10.1182/bloodadvances.2018026112.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00085124
• Other Study ID Numbers: NCI-2012-02805; CALGB-10201; CDR367323; U10CA031946 ( U.S. NIH Grant/Contract )
• First Posted: June 11, 2004
• Last Update Posted: June 5, 2013
• Last Verified: June 2013

Additional relevant MeSH terms:

Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Neoplasms by Histologic Type; Neoplasms; Cytarabine; Daunorubicin; Oblimersen; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antiviral Agents; Anti-Infective Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antibiotics, Antineoplastic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors