All-trans Retinoic Acid, and Arsenic +/- Idarubicin

Study Overview
=================
Brief Summary
-----------------
The goal of this clinical research study is to learn if the combination of arsenic trioxide (ATO) with ATRA and possibly idarubicin is effective in treating patients with newly-diagnosed APL.

Detailed Description
-----------------
All-trans retinoic acid (ATRA) and ATO are designed to cause the APL cells to mature and function normally. Idarubicin is designed to cause breaks in both strands of DNA (the genetic material of cells). If you are found to be eligible to take part in this study, you will begin induction. During induction, you will receive ATRA, by mouth starting on Day 1. You will also receive ATO through a needle in your vein over 2 hours starting on Day 1. You will continue receiving the drugs every day until your bone marrow no longer shows APL cells. If you had a high white blood cell count at screening, you will receive idarubicin through a needle in your vein over about 30 minutes one dose only on any day of Day 1 through 5. During induction, blood (about 1-3 tablespoons) will be drawn every day during Week 1, and then 2 times a week after that. This blood will be drawn for routine tests. During induction (about 21-28 days after beginning treatment), you will have a bone marrow aspirate to check the status of the disease. This may be performed more often if the doctor thinks it is needed. If you achieve a complete remission during the induction phase, you will continue to the maintenance phase. During the maintenance phase, you will receive ATO by vein over 2 hours Monday-Friday for 4 weeks. After the 4 weeks of receiving the study drug, you will have a 4-week period off (when no study drug is given). ATRA is given by mouth every day for 2 weeks. This 2 weeks is followed by 2 additional weeks when no study drug will be given. You will continue to take ATRA until treatment with ATO is complete. During maintenance, blood (about 1-3 tablespoons) will be drawn before every 4-week cycle of ATO, and then every week for routine tests. You will also have an ECG before every 4 week cycle when you take ATO. If you do not achieve a complete remission during induction you will be taken off study. If at any point during the study your white blood cell count rises above 10,000, you will receive idarubicin by vein over 30 minutes. You will remain in the hospital for about the first 7 days of induction. After that, you must remain in Houston for the next 3-4 weeks. Once in the maintenance phase, you may be treated at home, but must return to M. D. Anderson for study visits. After maintenance is complete, you will have follow-up visits for an additional 2 years. If at any time during the active study or follow-up the disease gets worse or intolerable side effects occur, you will be taken off the study. If you had a low or high white blood cell count when you joined the study, you will have follow-up visits every 3 months for 2 years. At these visits, blood (about 1 tablespoon) will be drawn for routine tests and you will have a bone marrow aspirate. This is an investigational study. Idarubicin, ATRA and ATO are FDA approved and commercially available. However, their use in this study and in this combination is considered investigational. Its use in APL patients is investigational. Up to 80 patients will take part in this multicenter study. All will be enrolled at M. D. Anderson.

Official Title
-----------------
Treatment of Acute Promyelocytic Leukemia (APL) With All-Trans Retinoic Acid, and Arsenic +/- Idarubicin

Conditions
-----------------
Acute Promyelocytic Leukemia

Intervention / Treatment
-----------------
* Drug: All-Trans Retinoic Acid (ATRA)
* Drug: Arsenic Trioxide (ATO)
* Drug: Idarubicin
* Drug: Gemtuzumab Ozogamicin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: A diagnosis of APL based on the presence of the PML-RAR alpha fusion gene by cytogenetics, PCR, or POD test. Provision of written informed consent. Patients in whom therapy for APL was initiated on an emergent basis are eligible Exclusion Criteria: First trimester of pregnancy (ATRA is teratogenic) Corrected QT (QTC) interval must not be greater than 480 milliseconds.
Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Induction ATRA + ATO + Idarubicin<br>All-Trans Retinoic Acid (ATRA) + Arsenic Trioxide (ATO) ATRA 45 mg/m2 daily by mouth beginning day 1; ATO 0.15 mg/kg by vein daily beginning on day 1; Idarubicin 12 mg/m2 x 1 dose; Methylprednisolone 50 mg daily for 5 days starting on day 1. | Drug: All-Trans Retinoic Acid (ATRA)<br>* Induction: 45 mg/m2 daily by mouth in 2 divided doses beginning day 1<br>Drug: Arsenic Trioxide (ATO)<br>* Induction: 0.15 mg/kg daily IV beginning day 1<br>Drug: Idarubicin<br>* 12 mg/m2 one dose only (may be given on day 1 to 5 of induction) If either ATRA or ATO are discontinued due to toxicity, idarubicin 12 mg/m2 x 2 doses will be administered once every 4 to 5 weeks (depending on the recovery of counts) until 28 weeks has elapsed from the Complete Recovery date.<br>* Other names: Idamycin;|
| Experimental: Maintenance<br>All-Trans Retinoic Acid (ATRA) + Arsenic Trioxide (ATO) ATO 0.15 mg/kg by vein over 2 hours Monday-Friday for 4 weeks, then a 4-week break. ATRA 45 mg/m2 by mouth every day for 2 weeks, followed by 2 additional weeks of no study drug. Continue ATRA until treatment with ATO complete. | Drug: All-Trans Retinoic Acid (ATRA)<br>* Induction: 45 mg/m2 daily by mouth in 2 divided doses beginning day 1<br>Drug: Arsenic Trioxide (ATO)<br>* Induction: 0.15 mg/kg daily IV beginning day 1<br>Drug: Idarubicin<br>* 12 mg/m2 one dose only (may be given on day 1 to 5 of induction) If either ATRA or ATO are discontinued due to toxicity, idarubicin 12 mg/m2 x 2 doses will be administered once every 4 to 5 weeks (depending on the recovery of counts) until 28 weeks has elapsed from the Complete Recovery date.<br>* Other names: Idamycin;|
| Experimental: Induction ATRA + ATO + GO<br>All-Trans Retinoic Acid (ATRA) + Arsenic Trioxide (ATO) + Gemtuzumab Ozogamicin (GO) ATRA 45 mg/m2 daily po (in 2 divided doses) beginning day 1; ATO 0.15 mg/kg IV daily beginning on day 1; GO 9 mg/m2 on day 1 Methylprednisolone 50 mg daily for 5 days followed by rapid taper starting on day 1. Theophylline 100mg p.o. bid days 1-3, 200 mg p.o. bid days 4-6, and 300 mg p.o. bid thereafter during periods when patient is receiving ATRA or ATO. Theophylline administration continues until therapy with ATO and ATRA is completed. | Drug: All-Trans Retinoic Acid (ATRA)<br>* Induction: 45 mg/m2 daily by mouth in 2 divided doses beginning day 1<br>Drug: Arsenic Trioxide (ATO)<br>* Induction: 0.15 mg/kg daily IV beginning day 1<br>Drug: Idarubicin<br>* 12 mg/m2 one dose only (may be given on day 1 to 5 of induction) If either ATRA or ATO are discontinued due to toxicity, idarubicin 12 mg/m2 x 2 doses will be administered once every 4 to 5 weeks (depending on the recovery of counts) until 28 weeks has elapsed from the Complete Recovery date.<br>* Other names: Idamycin;Drug: Gemtuzumab Ozogamicin<br>* Induction: 9 mg/m2 on day 1 of induction<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response (CR) Rate | Response defined as CR (marrow with <5% blasts and no abnormal promyelocytes together with neutrophil count >1000 and platelet count >100,000) and toxicity as Acute promyelocytic leukemia (APL) differentiation syndrome, arrhythmia, peripheral neuropathy. Bone marrow aspirate performed to check the status of the disease. | 1 month, up to day 85 of treatment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Acute Promyelocytic Leukemia, APL, ATRA, All-Trans Retinoic Acid, Arsenic Trioxide, Theophylline, Gemtuzumab