Combined Tretinoin and Arsenic Trioxide for Patients With Newly Diagnosed Acute Promyelocytic Leukemia Followed by Risk-Adapted Postremission Therapy

Condition(s) targeted: Acute Promyelocytic Leukemia

Intervention: Tretinoin and Arsenic Trioxide (Drug)

Phase: Phase 2

Status: Active, not recruiting

Sponsored by: Memorial Sloan Kettering Cancer Center

Official(s) and/or principal investigator(s):
Jae Park, MD, Principal Investigator, Affiliation: Memorial Sloan Kettering Cancer Center

The purpose of this study is to find what effects, good and/or bad, treatment with two drugs has on leukemia. The first medicine is tretinoin (also called all-trans retinoic acid, ATRA, or Vesanoid). It is an approved medicine that causes the leukemia cells in APL to mature. It is related to vitamin A. The second is arsenic trioxide (Trisenox). It is an approved medicine for APL that comes back after earlier treatment. APL is most often treated with tretinoin and standard chemotherapy drugs. These chemotherapy drugs can cause infection and bleeding. They can also damage the heart and normal bone marrow cells. This can lead to a second leukemia years later. In this study, the investigators are using tretinoin and arsenic trioxide together. Both drugs work to treat APL. They have been used together in only a limited number of people. The investigators want to use these drugs together to reduce the amount of standard chemotherapy and decrease side effects. The patient will receive standard chemotherapy with a drug called idarubicin only if they have a higher chance of the leukemia coming back or a higher risk of side effects.

Official title: Phase II Study of Combined Tretinoin and Arsenic Trioxide for Patients With Newly Diagnosed Acute Promyelocytic Leukemia Followed by Risk-Adapted Postremission Therapy

Study design: Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: To determine the rate of molecular remission

Secondary outcome:

To determine the rate of clinical complete remission (CR) and the time to remission

To determine the proportion of patients in molecular remission

To determine the disease-free, event-free, and overall survival of patients

To determine the toxicity of this treatment program

To characterize the differentiation of APL cells during treatment

Explore the in vivo induction of telomerase-dependent cell death

Detailed description: Induction will consist of tretinoin 45 mg/m2 po daily (rounded up to the nearest 10mg) in two divided doses (25 mg/m2 in patients <20 years of age) for 35 days and ATO 0. 15 mg/kg IV daily for 35 doses given 5-7 days per week. The drugs will then be discontinued, and the patient will be followed until a clinical complete remission is achieved. Idarubicin 12 mg/m2 IV for 4 doses will be added during induction on day 2 if the presenting WBC is >10,000/μl, or if the WBC increases to 5,000/μl on day 5, 10,000/μl on day 10, or 15,000/μl on day 15, because of the increased risk of the APL differentiation syndrome and relapse in these patients. Dexamethasone 10 mg twice daily with be given on days 1-14 of induction as prophylaxis for the APL differentiation syndrome. All patients will then receive four courses of consolidation with tretinoin 45 mg/m2 po daily (rounded up to the nearest 10mg) (25 mg/m2 in patients <20 years of age) for 15 days and ATO 0. 15 mg/kg IV for 25 doses. Patients with high-risk disease or who received Idarubicin during Induction may receive intrathecal cytarabine as CNS prophylaxis given by the treating physician during consolidation, at the discretion of the site PI. High-risk patients will also receive maintenance therapy with additional courses of tretinoin and ATO every 3 months for 2 years. Each maintenance course will consist of tretinoin 45 mg/m2 po daily (25 mg/m2 in patients <20 years of age) for 15 days and ATO 0. 15 mg/kg IV for 10 doses. Disease status will be monitored with serial analyses of peripheral blood samples using RT-PCR for PML-RARα mRNA. Patients will be followed until relapse, death, loss to follow-up, or removal from study. Induction therapy can be given as an inpatient or outpatient. Consolidation and maintenance treatments will be given as an outpatient. Consolidation may also be given at the patient's local institution. Intrathecal cytarabine treatments will be administered as an outpatient.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Previously untreated patients with a morphologic diagnosis of APL, confirmed by

demonstration of t(15;17) using conventional cytogenetics OR florescence in situ hybridization (FISH), OR a positive RT-PCR assay for PML-RAR at the subject's local institution.

- Age ≥18 years. Karnofsky performance status of ≥ 60%.

- Adequate renal function as demonstrated by a serum creatinine ≤ 2. 0 mg/dl or a

creatinine clearance of > 60 ml/min.

- Adequate hepatic function as demonstrated by a bilirubin < 2. 0 mg/dl (unless

attributable to Gilbert's disease) and an alkaline phosphatase, AST, and ALT ≤ 2. 5 times the upper limit of normal.

- Normal cardiac function as demonstrated by a left ventricular ejection fraction ≥ 50%

on echocardiogram or MUGA scan.

- QTc ≤ 500 msec on baseline ECG.

- Negative serum pregnancy test in women of childbearing potential.

- Ability to swallow oral medication.

- Men and women of child-bearing potential must be willing to practice an effective

method of birth control during treatment and at least 4 months after treatment is finished.

- Patients with central nervous system involvement by APL are eligible and may receive

concomitant treatment with radiation therapy and/or intrathecal chemotherapy in accordance with standard medical practice. Exclusion Criteria:

- Previous treatment for APL, except tretinoin, which may be given for up to 7 days

prior to study entry.

- Active serious infections not controlled by antibiotics.

- Pregnant women or women who are breast-feeding.

- Concurrent active malignancy requiring immediate therapy.

- Clinically significant cardiac disease (NY Heart Association Class III or IV),

including chronic arrhythmias, or pulmonary disease.

- Other serious or life-threatening conditions deemed unacceptable by the principal

investigator.

University of Southern California, Los Angeles, California 90033, United States

Northwestern University, Evanston, Illinois 60208, United States

National Heart, Lung, and Blood Institute (NIH), Bethesda, Maryland 20824, United States

Memorial Sloan Kettering at Basking Ridge, Basking Ridge, New Jersey 07920, United States

Memorial Sloan Kettering Cancer Center @ Suffolk, Commack, New York 11725, United States

Memorial Sloan Kettering Cancer Center, New York, New York 10065, United States

New York Presbyterian Hospital-Weill Medical College of Cornell University, New York, New York 10065, United States

Memorial Sloan Kettering at Mercy Medical Center, Rockville Centre, New York, United States

Memorial Sloan Kettering Cancer Center at Phelps Memorial Hospital Center, Sleepy Hollow, New York 10591, United States

Memorial Sloan Kettering West Harrison, West Harrison, New York 10604, United States

Cleveland Clinic, Cleveland, Ohio 44195, United States

Princess Margaret Hospital/Ontario Cancer Institute, Toronto, Ontario, Canada

Memorial Sloan Kettering Cancer Center

Starting date: July 2011
Last updated: August 19, 2015