Clinical trial NCT01404949: Combined Tretinoin and Arsenic Trioxide for Patients With Newly Diagnosed Acute Promyelocytic Leukemia Followed by Risk-Adapted Postremission Therapy
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acute Promyelocytic Leukemia
Keywords: Tretinoin
all-trans retinoic acid
ATRA
Vesanoid
Arsenic Trioxide
ATO
Trisenox
11-040
Lead sponsor: Memorial Sloan Kettering Cancer Center
Sponsor class: OTHER
Collaborators: name: Northwestern University
name: New York Presbyterian Hospital
name: University of Southern California
name: Princess Margaret Hospital, Canada
name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2011-07-28
Enrollment: 17
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility 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.

Primary outcomes:
measure: To Determine the Rate of Molecular Remission
timeFrame: 4 years
Secondary outcomes:
measure: Participants Who Experienced a Complete Remission
timeFrame: 4 years
measure: To Determine the Proportion of Patients in Molecular Remission
timeFrame: 4 years
measure: To Determine the Disease-free and Event-free Survival of Patients
timeFrame: 4 years
measure: To Determine the Toxicity of This Treatment Program
timeFrame: 4 years
measure: To Characterize the Differentiation of APL Cells During Treatment
timeFrame: 4 years
measure: Explore the in Vivo Induction of Telomerase-dependent Cell Death
timeFrame: 4 years
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: Evanston
country: United States
facility: Northwestern University
state: Illinois
city: Bethesda
country: United States
facility: National Heart, Lung, and Blood Institute (NIH)
state: Maryland
city: Basking Ridge
country: United States
facility: Memorial Sloan Kettering at Basking Ridge
state: New Jersey
city: Middletown
country: United States
facility: Memorial Sloan Kettering Monmouth
state: New Jersey
city: Commack
country: United States
facility: Memorial Sloan Kettering Cancer Center @ Suffolk
state: New York
city: Harrison
country: United States
facility: Memorial Sloan Kettering Westchester
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: New York
country: United States
facility: New York Presbyterian Hospital-Weill Medical College of Cornell University
state: New York
city: Rockville Centre
country: United States
facility: Memorial Sloan Kettering at Mercy Medical Center
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Toronto
country: Canada
facility: Princess Margaret Hospital/Ontario Cancer Institute
state: Ontario
Study officials:
affiliation: Memorial Sloan Kettering Cancer Center
name: Jae Park, MD
role: PRINCIPAL_INVESTIGATOR
References: