Tretinoin, Cytarabine, and Daunorubicin Hydrochloride With or Without Arsenic Trioxide Followed by Tretinoin With or Without Mercaptopurine and Methotrexate in Treating Patients With Acute Promyelocytic Leukemia

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ClinicalTrials.gov Identifier: NCT00003934

Recruitment Status : Completed

First Posted : January 27, 2003

Last Update Posted : June 5, 2013

Sponsor:

Information provided by (Responsible Party):

National Cancer Institute (NCI)

Study Description

Brief Summary:

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. 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.

Condition or disease	Intervention/treatment	Phase
Adult Acute Myeloid Leukemia With t(15;17)(q22;q12) Adult Acute Promyelocytic Leukemia (M3) Childhood Acute Promyelocytic Leukemia (M3) Untreated Adult Acute Myeloid Leukemia Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies	Drug: tretinoin Drug: daunorubicin hydrochloride Drug: cytarabine Drug: mercaptopurine Drug: methotrexate Drug: arsenic trioxide	Phase 3

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Detailed Description:

PRIMARY OBJECTIVES:

i. To compare the efficacy (event-free survival) and toxicities of two induction/consolidation therapies for patients with untreated APL: ATRA/ara-C/daunorubicin with or without arsenic trioxide (As2O3).

II. To evaluate the efficacy (disease-free survival) and toxicities of maintenance therapy with intermittent ATRA vs intermittent ATRA plus 6-MP/MTX for patients with APL who achieve a complete response.

III. To explore the relationship between CD56 expression at diagnosis and clinical outcomes.

IV. To evaluate the cardiac toxicity of intensive daunorubicin therapy, as given in this study, to 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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	420 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
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 Maintenance Therapy With Intermittent Tretinoin Versus Intermittent Tretinoin Plus Mercaptopurine and Methotrexate for Patients With Untreated Acute Promyelocytic Leukemia
Study Start Date :	June 1999
Actual Primary Completion Date :	November 2006

Resource links provided by the National Library of Medicine

Genetics Home Reference related topics: Acute promyelocytic leukemia Core binding factor acute myeloid leukemia Cytogenetically normal acute myeloid leukemia Familial acute myeloid leukemia with mutated CEBPA

MedlinePlus related topics: Arsenic Leukemia

Drug Information available for: Mercaptopurine Methotrexate Tretinoin Arsenic trioxide Arsenic Daunorubicin Daunorubicin hydrochloride

Genetic and Rare Diseases Information Center resources: Myeloid Leukemia Acute Myeloid Leukemia Acute Non Lymphoblastic Leukemia Acute Promyelocytic Leukemia

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm I 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 CR or 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. 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.	Drug: tretinoin Given orally Other Names: ATRA Retin-A TRA Drug: daunorubicin hydrochloride Given IV Other Names: Cerubidin Cerubidine daunomycin hydrochloride daunorubicin RP-13057 Drug: cytarabine Given IV Other Names: ARA-C arabinofuranosylcytosine arabinosylcytosine Cytosar-U cytosine arabinoside Drug: arsenic trioxide Given IV Other Names: Arsenic (III) Oxide Arsenic Sesquioxide Arsenous Acid Anhydride AS2O3 Trisenox
Experimental: Arm II 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 CR or 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. 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.	Drug: tretinoin Given orally Other Names: ATRA Retin-A TRA Drug: daunorubicin hydrochloride Given IV Other Names: Cerubidin Cerubidine daunomycin hydrochloride daunorubicin RP-13057 Drug: cytarabine Given IV Other Names: ARA-C arabinofuranosylcytosine arabinosylcytosine Cytosar-U cytosine arabinoside Drug: mercaptopurine Given IV Other Names: 6-mercaptopurine 6-MP Leukerin MP Drug: methotrexate Given IV Other Names: amethopterin Folex methylaminopterin Mexate MTX Drug: arsenic trioxide Given IV Other Names: Arsenic (III) Oxide Arsenic Sesquioxide Arsenous Acid Anhydride AS2O3 Trisenox

Arm

Intervention/treatment

Experimental: Arm I

Consolidation: All patients achieving CR or 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.

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.

Drug: tretinoin

Given orally

Other Names:

ATRA
Retin-A
TRA

Drug: daunorubicin hydrochloride

Given IV

Other Names:

Cerubidin
Cerubidine
daunomycin hydrochloride
daunorubicin
RP-13057

Drug: cytarabine

Given IV

Other Names:

ARA-C
arabinofuranosylcytosine
arabinosylcytosine
Cytosar-U
cytosine arabinoside

Drug: arsenic trioxide

Given IV

Other Names:

Arsenic (III) Oxide
Arsenic Sesquioxide
Arsenous Acid Anhydride
AS2O3
Trisenox

Experimental: 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.

Drug: tretinoin

Given orally

Other Names:

ATRA
Retin-A
TRA

Drug: daunorubicin hydrochloride

Given IV

Other Names:

Cerubidin
Cerubidine
daunomycin hydrochloride
daunorubicin
RP-13057

Drug: cytarabine

Given IV

Other Names:

ARA-C
arabinofuranosylcytosine
arabinosylcytosine
Cytosar-U
cytosine arabinoside

Drug: mercaptopurine

Given IV

Other Names:

6-mercaptopurine
6-MP
Leukerin
MP

Drug: methotrexate

Given IV

Other Names:

amethopterin
Folex
methylaminopterin
Mexate
MTX

Drug: arsenic trioxide

Given IV

Other Names:

Arsenic (III) Oxide
Arsenic Sesquioxide
Arsenous Acid Anhydride
AS2O3
Trisenox

Outcome Measures

Primary Outcome Measures :

Response rates [ Time Frame: Up to 10 years ]
Distributions of event-free survival [ Time Frame: Up to 10 years ]
Disease-free survival [ Time Frame: Time from the date of the maintenance randomization to relapse or death, assessed up to 10 years ]
Survival [ Time Frame: Up to 10 years ]
Toxicities for the various therapies graded according to the National Cancer Institute Common Toxicity Criteria (NCI CTC) v2.0 [ Time Frame: Up to 30 days after last dose of study treatment ]

Eligibility Criteria

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Ages Eligible for Study:	Child, Adult, Older Adult
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Patients must have a clinical diagnosis of acute promyelocytic leukemia (APL) with proof of APL morphology (FAB-M3) confirmed by RT-PCR assay; a patient may be entered prior to completion of RT-PCR studies, but a patient who is subsequently found to be PML-RARα negative and RARα-PML negative will be removed from protocol treatment
FAB clasification: the aspirate smear must show M3 characteristics and at least 30% of cells must be abnormal promyelocytes with heavy granulation; the overall marrow cellularity must be normocellular or hypercellular; patients with the microgranular variant (M3V) are eligible, and the diagnosis will be based on characteristic morphologic findings (e.g., reniform or bilobed nuclei)
RT-PCR assay: submission of samples for RT-PCR assays for PML-RARα/RARα-PML transcripts is mandatory; the results do not have to be known prior to initiation of therapy; if the assay is subsequently found to be negative, the patient will be removed from protocol treatment and treated at the discretion of the responsible physician
Prior treatment: the patient must not have received any systemic definitive treatment for APL, including cytotoxic chemotherapy or retinoids; prior therapy with corticosteroids, hydroxyurea or leukapheresis will not exclude the patient
Non-pregnant, non-nursing: treatment under this protocol would expose an unborn child to significant risks; patients should not be pregnant or plan to become pregnant while on treatment; women and men of reproductive potential should agree to use an effective means of birth control; there is an extremely high risk of fetal malformation if pregnancy occurs while on ATRA in any amount even for short periods

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00003934

Locations

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United States, Illinois
Cancer and Leukemia Group B
Chicago, Illinois, United States, 60606
United States, North Carolina
Comprehensive Cancer Center of Wake Forest University
Winston-Salem, North Carolina, United States, 27157

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

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Principal Investigator:	Bayard Powell	Cancer and Leukemia Group B

More Information

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

Powell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM, Rowe JM, Coutre S, Feusner JH, Gregory J, Couban S, Appelbaum FR, Tallman MS, Larson RA. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010 Nov 11;116(19):3751-7. doi: 10.1182/blood-2010-02-269621. Epub 2010 Aug 12.

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Responsible Party:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00003934
Other Study ID Numbers:	NCI-2012-02811 C9710 CDR0000067126 CALGB-C9710 U10CA031946 ( U.S. NIH Grant/Contract )
First Posted:	January 27, 2003 Key Record Dates
Last Update Posted:	June 5, 2013
Last Verified:	June 2013

Additional relevant MeSH terms:

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Leukemia Leukemia, Myeloid Leukemia, Myeloid, Acute Leukemia, Promyelocytic, Acute Neoplasms by Histologic Type Neoplasms Cytarabine Methotrexate Mercaptopurine Daunorubicin Arsenic Trioxide Tretinoin Abortifacient Agents, Nonsteroidal Abortifacient Agents Reproductive Control Agents	Physiological Effects of Drugs Antimetabolites, Antineoplastic Antimetabolites Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Dermatologic Agents Enzyme Inhibitors Folic Acid Antagonists Immunosuppressive Agents Immunologic Factors Antirheumatic Agents Nucleic Acid Synthesis Inhibitors Antiviral Agents Anti-Infective Agents Antibiotics, Antineoplastic

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