Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

Tretinoin and Arsenic Trioxide With or Without Idarubicin in Treating Patients With Acute Promyelocytic Leukemia

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase II Treatment Active 18 and over NCI, Pharmaceutical / Industry MSKCC-07108 IRB 07-108, CEPHALONO-MSKCC-07108, NCT00528450

Objectives

Primary

1. To determine the rate of molecular remission after induction therapy comprising tretinoin (ATRA) and arsenic trioxide (ATO) (along with idarubicin in patients with leukocytosis) in patients with acute promyelocytic leukemia (APL).

Secondary

1. To determine the rate of clinical complete remission and the time to remission after induction therapy.
2. To determine the proportion of patients in molecular remission after each course of postremission therapy and to use these findings to direct the number of consolidation courses with ATRA and idarubicin that are administered.
3. To determine the disease-free survival and overall survival of patients treated with this regimen.
4. To determine the toxicity of this treatment regimen, including the number and length of hospitalizations, the incidence of secondary myelodysplastic syndromes or acute myeloid leukemia, and the effects of treatment on LVEF.
5. To characterize the differentiation of APL cells during treatment with combined ATRA and ATO using serial immunophenotyping studies of peripheral blood and bone marrow.
6. To compare the results of quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assays performed on bone marrow and peripheral blood.

Entry Criteria

Disease Characteristics:

• Morphologic diagnosis of acute promyelocytic leukemia (APL), confirmed by one of the following:
  • Demonstration of t(15;17) using conventional cytogenetics or fluorescence in situ hybridization (FISH)
  • Positive PML-RARα transcript by reverse transcriptase-polymerase chain reaction (RT-PCR) assay



• Patients with CNS involvement by APL are eligible

Prior/Concurrent Therapy:

• No prior treatment for APL

Patient Characteristics:

• Karnofsky performance status 60-100%
• Creatinine ≤ 2.0 mg/dL or creatinine clearance > 60 mL/min
• Bilirubin < 2.0 mg/dL (unless attributed to Gilbert disease)
• Alkaline phosphatase ≤ 2.5 times the upper limit of normal (ULN)
• AST and ALT ≤ 2.5 ULN
• LVEF ≥ 50% on echocardiogram or MUGA scan
• QTc ≤ 500 msec on baseline ECG
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for ≥ 4 months after the completion of study treatment
• No active serious infections not controlled by antibiotics
• No other concurrent active malignancy requiring immediate therapy
• No clinically significant cardiac disease (New York Heart Association class III or IV heart disease), including chronic arrhythmias
• No pulmonary disease
• No other serious or life-threatening condition deemed unacceptable by the principal investigator

Expected Enrollment

Outcomes

Molecular remission rate

Clinical complete remission rate
Proportion of patients who negative for disease by RT-PCR at study entry, after induction therapy, after each course of tretinoin (ATRA) and arsenic trioxide, and after each course of ATRA and idarubicin
Median time to clinical and molecular remissions
Disease-free survival
Overall survival
Toxicity as measured by NCI CTCAE version 3.0
Number of hospitalizations and number of hospital days
Incidence of secondary myelodysplastic syndromes/acute myeloid leukemia
Comparison of the results of quantitative real-time RT-PCR assays for the PML-RARα transcript on bone marrow and peripheral blood
Correlation of immunophenotyping of peripheral blood during induction therapy with expression of surface antigens, including CD33 and CD11b, over time

Outline

• Induction therapy: Patients receive tretinoin orally twice daily and arsenic trioxide IV over 1-4 hours once daily until a marrow remission is documented or for 60 days, whichever comes first. Patients with leukocytosis (WBC > 10,000/μL) also receive idarubicin IV over 10-15 minutes beginning on day 2 and continuing every other day for 4 doses. Patients who achieve a clinical complete remission (CR) proceed to consolidation therapy. If a marrow remission is not achieved after 60 days, the patient is removed from the study.



• Consolidation therapy:
  • Consolidation courses 1, 2, and 3: Beginning 3-6 weeks after documentation of clinical CR, patients receive consolidation therapy comprising tretinoin orally twice daily for 15 days and arsenic trioxide IV over 1-4 hours once daily 5 days a week for 5 weeks. Consolidation therapy repeats every 3-6 weeks for 3 courses.

    Patients who have a negative PML-RARα transcript by reverse transcriptase-polymerase chain reaction (RT-PCR) assay after consolidation course 2 proceed to maintenance therapy after receiving consolidation course 3. Patients who have a negative PML-RARα transcript by RT-PCR assay after consolidation course 3, proceed to consolidation course 4 followed by maintenance therapy. Patients who have a positive PML-RARα transcript by RT-PCR assay after consolidation courses 2 and 3 proceed to consolidation courses 4 and 5.

  
  
  
  • Consolidation course 4: Beginning 3-6 weeks after completion of consolidation course 3, patients receive tretinoin orally twice daily for 15 days and idarubicin IV over 10-15 minutes once daily for 4 days.
  
  
  
  • Consolidation course 5: Beginning 3-6 weeks after completion of consolidation course 4, patients receive tretinoin orally twice daily for 15 days and idarubicin IV over 10-15 minutes once daily for 3 days.

    Patients who remain positive for the PML-RARα transcript after 5 courses of consolidation therapy are removed from the study. Patients who have a negative PML-RARα transcript after 5 courses of consolidation therapy proceed to maintenance therapy.

  
  
  



• Maintenance therapy: Beginning approximately 3 months after completion of the final consolidation course, patients receive tretinoin orally twice daily for 15 days. Treatment repeats every 3 months for up to 2 years.

After completion of study therapy, patients are followed periodically.

Trial Contact Information

Trial Lead Organizations

Memorial Sloan-Kettering Cancer Center

Joseph Jurcic, MD, Principal investigator		Ph: 212-639-2955; 800-525-2225 Email: jurcicj@mskcc.org
Peter Maslak, MD, Principal investigator		Ph: 212-639-5518; 800-525-2225 Email: maslakp@mskcc.org

U.S.A.
New York
	New York
	Memorial Sloan-Kettering Cancer Center
		Joseph Jurcic, MD	Ph:  212-639-2955 800-525-2225
			Email: jurcicj@mskcc.org

Registry Information
Official Title		Phase II Study of Combined All-Trans Retinoic Acid and Arsenic Trioxide for Acute Promyelocytic Leukemia Followed by Risk-Adapted Postremission Therapy
Trial Start Date		2007-09-20
Trial Completion Date		2012-12-10 (estimated)
Registered in ClinicalTrials.gov		NCT00528450
Date Submitted to PDQ		2007-08-16
Information Last Verified		2008-12-14
NCI Grant/Contract Number		CA08748

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