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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


Phase 3
N/A
N/A
Not Enrolling
Both
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

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Trial Information

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


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.


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

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Response rates

Outcome Time Frame:

Up to 10 years

Safety Issue:

No

Principal Investigator

Bayard Powell

Investigator Role:

Principal Investigator

Investigator Affiliation:

Cancer and Leukemia Group B

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2012-02811

NCT ID:

NCT00003934

Start Date:

June 1999

Completion Date:

Related Keywords:

  • 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
  • Neoplasms
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Promyelocytic, Acute

Name

Location

Comprehensive Cancer Center of Wake Forest UniversityWinston-Salem, North Carolina  27157-1082
Cancer and Leukemia Group BChicago, Illinois  60606