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9L-12-1: Phase II Study of Combined Tretinoin and Arsenic Trioxide for Patients with Newly Diagnosed Acute Promyelocytic Leukemia Followed by Risk-Adapted Postremission Therapy

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.

Phase

Phase 2 - takes the treatment one step further, assessing the activity of a particular therapy in a disease, often building upon leads from the Phase I trial. While patients are generally required to be previously untreated, participation in a Phase II trial doesn't usually preclude the patient from getting the standard treatment after they've received the investigational agent. At best they are allowed to get a new drug they wouldn't be able to get otherwise that may turn out to be better for their disease.

Inclusion and Exclusion 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.

  • 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.

Sites

  • California

    • University of Southern California, Los Angeles, California, 90033
  • Illinois

    • Northwestern University, Evanston, Illinois, 60208
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