Official Title: “Phase III Randomized Study of Concurrent Tretinoin and Chemotherapy With or Without Arsenic Trioxide (As2O3) (NSC# 706363) as Initial Consolidation Therapy Followed by Intermittent Tretinoin Maintenance Therapy Versus Observation for Patients With Untreated Acute Promyelocytic Leukemia”

RATIONALE: Drugs used in chemotherapy, such as daunorubicin, cytarabine, mercaptopurine, methotrexate, and arsenic trioxide, work in different ways to stop cancer cells from dividing so they stop growing or die. Tretinoin may help leukemia cells develop into normal white blood cells. It is not yet known which regimen is more effective for acute promyelocytic leukemia.

PURPOSE: This randomized phase III trial is studying tretinoin and combination chemotherapy to see how well they work compared to tretinoin, combination chemotherapy, and arsenic trioxide in treating patients with acute promyelocytic leukemia that has not been treated previously.

Study Type: Interventional

Study Design: Treatment, Randomized, Active Control

OBJECTIVES: - Compare the efficacy (event-free survival) and toxicity of tretinoin, cytarabine, and daunorubicin with or without arsenic trioxide as induction/consolidation therapy in patients with previously untreated acute promyelocytic leukemia. - Evaluate the efficacy (disease-free survival) and toxicity of intermittent tretinoin with or without mercaptopurine and methotrexate as maintenance therapy in these patients who achieve a complete response after induction/consolidation therapy. - Determine the relationship between CD56 expression at diagnosis and clinical outcomes in these patients treated with this regimen. - Evaluate the cardiac toxicity of intensive daunorubicin therapy in pediatric patients.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to age (under 15 vs 15 to 60 vs over 60) for the induction phase.

Patients are stratified according to age, as in the induction phase, and the consolidation arm (with vs without arsenic trioxide) for the consolidation phase. Patients under age 5 do not receive arsenic trioxide. - Induction: All patients receive oral tretinoin every 12 hours beginning on day 1 until complete response or for a maximum of 90 days. Patients also receive daunorubicin IV on days 3-6 and cytarabine IV continuously on days 3-9. - Consolidation: All patients achieving complete response (CR), or partial response (PR) after completion of tretinoin, proceed to consolidation within 2 weeks of achieving CR or PR, but not prior to 30 days from the start of induction. Patients are randomized to 1 of 2 treatment arms. - Arm I: Patients receive oral tretinoin every 12 hours on days 1-7 and daunorubicin IV on days 1-2 or days 1-3, depending on age. Patients may receive an additional course. Treatment begins no earlier than 2 weeks and no later than 4 weeks after hematopoietic recovery. - Arm II: Patients receive arsenic trioxide IV over 2 hours daily 5 days a week for 5 weeks. After a 2-week rest, patients receive a second course of arsenic trioxide.

Patients then receive tretinoin and daunorubicin as in arm I. - Maintenance: Patients maintaining CR or PR after consolidation therapy proceed to maintenance therapy, beginning no earlier than 2 weeks and no later than 4 weeks after hematopoietic recovery. Patients are randomized to 1 of 2 treatment arms. - Arm I: Patients receive oral tretinoin every 12 hours for 7 days every other week for 1 year. - Arm II: Patients receive oral tretinoin as in arm I above. Patients also receive oral mercaptopurine once a day and oral methotrexate once weekly for up to 1 year.

Maintenance therapy continues for up to 1 year in the absence of unacceptable toxicity.

Patients are followed every 2 months for 2 years, every 3 months for 1 year, every 6 months for 2 years, and then annually for 5 years.

PROJECTED ACCRUAL: A total of 522 patients (456 adults and 66 pediatric) will be accrued for this study within 4.75 years.

Intervention(s) in this Clinical Trial

• Drug: arsenic trioxide
• Drug: cytarabine
• Drug: daunorubicin hydrochloride
• Drug: mercaptopurine
• Drug: methotrexate
• Drug: tretinoin

DISEASE CHARACTERISTICS:

• Clinically diagnosed, previously untreated acute promyelocytic leukemia (APL) with proof of APL morphology (FAB-M3) confirmed by reverse transcriptase polymerase chain reaction
• M3 characteristics by aspirate smear
• At least 30% of cells must be abnormal promyelocytes with heavy granulation
• Overall marrow cellularity must be normocellular or hypercellular
• Microgranular variant (M3V) eligible

PATIENT CHARACTERISTICS:

Age:

• Any age

Performance status:

• Not specified

Life expectancy:

• Not specified

Hematopoietic:

• Not specified

Hepatic:

• Not specified

Renal:

• Not specified

Other:

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• No concurrent growth factors, except filgrastim (G-CSF) or sargramostim (GM-CSF) for life-threatening clinical deterioration (e.g., severe pneumonia, hypotension, multiorgan dysfunction, or fungal infection)

Chemotherapy:

• No prior cytotoxic chemotherapy for APL
• Prior hydroxyurea allowed

Endocrine therapy:

• Prior corticosteroids allowed

Radiotherapy:

• No concurrent palliative radiotherapy

Surgery:

• Not specified

Other:

• Prior leukapheresis allowed
• No prior retinoids for APL

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: N/A

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Cancer and Leukemia Group B

Overall Clinical Trial Officials and Contacts

Bayard L. Powell, MD Study Chair Wake Forest University  

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00003934

Study ID Number: CDR0000067126

ClinicalTrials.gov Identifier: NCT00003934

Health Authority: United States: Federal Government

Clinical trial summary from the National Cancer Institute's PDQ® database