S0106 Cytarabine and Daunorubicin w/ or w/o Gemtuzumab Followed By HD Cytarabine and Either Gemtuzumab or Nothing in de Novo AML

SWOG Cancer Research Network

Status and phase: Completed; Phase 3

Conditions: Leukemia

Treatments: Other: observation; Drug: Daunomycin; Drug: gemtuzumab ozogamicin; Drug: Cytosine arabinoside

Study type: Interventional

Funder types: NETWORK; NIH

Identifiers

NCT00085709

S0106 (Other Identifier)

U10CA032102 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

RATIONALE: Drugs used in chemotherapy, such as cytarabine and daunorubicin, work in different ways to stop cancer cells from dividing so they stop growing and die. Monoclonal antibodies, such as gemtuzumab ozogamicin, can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. Combining chemotherapy with gemtuzumab ozogamicin may kill more cancer cells. It is not yet known whether induction therapy using cytarabine and daunorubicin is more effective with or without gemtuzumab ozogamicin or whether postconsolidation therapy using gemtuzumab ozogamicin is more effective than no additional therapy in treating de novo (first occurrence) acute myeloid leukemia.

PURPOSE: This randomized phase III trial is comparing two different regimens of chemotherapy and monoclonal antibody therapy to see how well they work in treating patients with previously untreated de novo acute myeloid leukemia.

Full description

OBJECTIVES:

• Compare disease-free survival of patients with previously untreated de novo acute myeloid leukemia treated with induction therapy comprising cytarabine and daunorubicin with vs without gemtuzumab ozogamicin followed by consolidation therapy comprising high-dose cytarabine and post-consolidation therapy comprising gemtuzumab ozogamicin vs no additional therapy.
• Compare the complete remission rate in patients treated with these regimens.
• Compare the frequency and severity of the toxic effects of these regimens in these patients.

Other objectives (if funding allows):

• Determine the prognostic significance of CD33 expression on the response rate in patients receiving gemtuzumab ozogamicin.
• Determine the prognostic significance of FLT3 mutations in these patients before treatment with these regimens.
• Determine the prognostic significance of minimal residual disease in remission specimens from these patients treated with these regimens.
• Determine the prognostic significance of the flow cytometric detection of minimal residual disease in specimens collected from these patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified during induction therapy according to age (< 35 years vs ≥ 35 years) and during post-consolidation therapy according to preinduction cytogenetic risk group.

• Induction therapy: Patients are randomized to 1 of 2 treatment arms.

  • Arm I: Patients receive daunorubicin IV on days 1-3, cytarabine IV continuously on days 1-7, and gemtuzumab ozogamicin IV over 2 hours on day 4. Patients receive filgrastim (G-CSF) or sargramostim (GM-CSF) IV or subcutaneously once daily beginning on day 15 and continuing until blood counts recover.
  • Arm II: Patients receive daunorubicin, cytarabine, and G-CSF or GM-CSF as in arm I.

Patients in both arms undergo bone marrow aspiration and biopsy on day 14 (and on day 19, if applicable) and then proceed to reinduction therapy.

• Reinduction therapy: Patients receive daunorubicin IV on days 1-3 and cytarabine IV continuously on days 1-7. Patients also receive G-CSF or GM-CSF as in induction therapy.

Patients who achieve A1 bone marrow, B1 peripheral blood, and C1 extramedullary disease status proceed to consolidation therapy.

• Consolidation therapy: Patients receive high-dose cytarabine IV over 3 hours twice daily on days 1, 3, and 5. Treatment repeats every 28 days for 3 courses in the absence of disease progression or unacceptable toxicity.

Patients who maintain A1 bone marrow, B1 peripheral blood, and C1 extramedullary disease status after consolidation therapy proceed to post-consolidation therapy.

• Post-consolidation therapy: Patients are randomized to 1 of 2 treatment arms.

  • Arm I: Patients receive gemtuzumab ozogamicin IV over 2 hours on day 1. Treatment repeats every 28 days for 3 courses in the absence of disease progression or unacceptable toxicity.
  • Arm II: Patients receive no additional therapy. Patients are observed at days 30 and 60 after randomization.

Patients are followed every 3 months for 1 year, every 6 months for 1 year, and then annually for 3 years.

PROJECTED ACCRUAL: A total of 684 patients (342 per treatment arm) will be accrued for this study within 4.5-5 years.

Enrollment: 637 patients

Sex: All

Ages: 18 to 60 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

DISEASE CHARACTERISTICS:

• Morphologically confirmed acute myeloid leukemia (AML) by bone marrow aspiration and biopsy* within the past 14 days

  • No M3 disease NOTE: *Patients with marked leukocytosis may be registered before the availability of biopsy results if the absolute blast count is ≥ 100,000 cells/µL

• No blastic transformation of chronic myelogenous leukemia

• No pre-existing hematologic disorder evolving to AML (e.g., myelodysplasia or secondary leukemia)

PATIENT CHARACTERISTICS:

Age

• 18 to 60

Performance status

• Zubrod 0-3

Life expectancy

• Not specified

Hematopoietic

• See Disease Characteristics

Hepatic

• Bilirubin ≤ 2 times upper limit of normal (ULN)
• AST and ALT ≤ 3 times ULN
• No known hepatitis B or C infection
• No known liver disease

Renal

• Not specified

Cardiovascular

• LVEF ≥ 50% by MUGA or echocardiogram
• No unstable cardiac arrhythmias
• No unstable angina

Other

• No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, or adequately treated stage I or II cancer currently in complete remission
• Not pregnant or nursing
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• No prior systemic chemotherapy

  • Prior hydroxyurea to control high cell counts allowed

• No more than 1 prior dose of intrathecal chemotherapy for acute leukemia

• Concurrent intrathecal chemotherapy allowed during induction therapy

Endocrine therapy

• Not specified

Radiotherapy

• Not specified

Surgery

• Not specified

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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637 participants in 4 patient groups

Post-consolidation GO

Experimental group

Description:

Patients receive gemtuzumab ozogamicin IV over 2 hours on day 1. Treatment repeats every 28 days for 3 courses in the absence of disease progression or unacceptable toxicity.

Treatment:

Drug: gemtuzumab ozogamicin

Post-consolidation observation

Other group

Description:

Patients receive no additional therapy. Patients are observed at days 30 and 60 after randomization.

Treatment:

Other: observation

Induction 7+3

Active Comparator group

Description:

Standard induction regimen of 7 days of Ara-C (cytosine arabinoside) and 3 days of daunomycin

Treatment:

Drug: Cytosine arabinoside

Drug: Daunomycin

Induction 7+3+GO

Active Comparator group

Description:

Gemtuzumab (GO) added to the standard induction regimen of 7 days of Ara-C and 3 days of daunomycin

Treatment:

Drug: Cytosine arabinoside

Drug: Daunomycin