Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Related Publications
Trial Contact Information

Alternate Title

Combination Chemotherapy With or Without PSC 833 in Treating Patients With Recurrent or Refractory Acute Myelogenous Leukemia or High Risk Myelodysplastic Syndrome

Basic Trial Information

Objectives

I. Compare the complete remission rate of mitroxantrone/etoposide/cytarabine
(MEC) to MEC plus PSC 833 (PSC MEC) in patients with recurrent or refractory 
acute myeloid leukemia and high risk myelodysplastic syndrome.

II. Determine and compare the incidence and severities of toxic effects of 
these two regimens.

III. Correlate mdr1 gene expression in tumor specimens with response of the 
leukemias to therapy.

IV. Examine the duration of disease free survival of the responding patients 
treated with PSC MEC versus that of responding patients treated with MEC.

Entry Criteria

Disease Characteristics:

Morphologically proven recurrent or refractory acute myeloid leukemia (acute
 myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic     
  leukemia, acute monocytic leukemia, acute erythroleukemia, and acute         
   megakaryocytic leukemia) OR

High risk myelodysplastic syndromes:
  Refractory anemia with excess blasts (RAEB) in transformation
  RAEB with greater than 10% marrow blasts and poor risk cytogenetics or
   bi/pancytopenia
  Both groups must have stability or deterioration of their blood counts
   and/or marrow findings for the past 4 weeks and dysplasia of at least 2
   hemopoietic cell lines

Patient must qualify for at least one of the following factors:
   Relapse no greater than 6 months after first complete response
 
   Refractory to conventional initial induction chemotherapy or to first       
     reinduction
 
   Relapse after allogeneic or autologous bone marrow transplant (ABMT) 
    ABMT patients must have no evidence of prior poor stem cell reserve
 
   Second or greater relapse
 
   Secondary acute myeloid leukemia (AML) or AML evolving from myelodysplastic 
     syndrome or myeloproliferative disorder

Myelodysplastic syndrome must be within 4 weeks prior to induction therapy

AML must be within 2 weeks of induction therapy

Prior CNS disease is allowed if there is no current CNS involvement
    

Prior/Concurrent Therapy:

Biologic therapy:
 Not specified
 
Chemotherapy:
 No prior chemotherapy within 4 weeks of study (except for patients            
   refractory to induction chemotherapy)
 Prior doxorubicin, daunorubicin, idarubicin, and mitoxantrone is allowed
 No prior mitoxantrone, etoposide, and cytarabine combination regimen

Endocrine therapy:
 Not specified

Radiotherapy:
 No prior radiation therapy within 4 weeks of study (except for patients       
   refractory to induction chemotherapy)

Surgery:
 Not specified

Other:
 Ineligible if receiving concurrent treatment with the following agents        
   (therapy should be discontinued 24 hours prior to PSC 833 induction):
  Bromocriptine       Danazol            Diltiazem
  Erythromycin        Fluconazole        Itraconazole
  Ketoconazole        Nicardipine        Methylprednisolone        
  Pristinamycin       Verapamil          Metoclopramide
  Carbamezepine       Phenobarbitol      Phenytoin
  Rifampin            Ticlopidine        Nafcillin
    

Patient Characteristics:

Age:
 15 to 70

Performance Status:
 ECOG 0-2

Hematopoietic:
 Absolute neutrophil count at least 1,500/mm3
 Platelet count at least 100,000/mm3

Hepatic:
 Bilirubin less than 1.5 mg/dL 
 SGOT less than 2 times upper limit of normal

Renal:
 Creatinine less than 1.8 mg/dL

Cardiovascular:
 No history of recent myocardial infarction within 3 months of study
 No significant congestive heart failure
 No significant cardiac arrhythmias
 Cardiac ejection fraction at least 50% or at least a 5% increase with
  exercise (MUGA scan)

Other:
 Not pregnant or nursing
 Effective contraceptive method must be used during study
 No concurrent organ damage or medical illness
 No active or unresolved infections
 No prior or concurrent invasive fungal infections
 No hypersensitivity to Cremophor EL or other study medication ingredients

Expected Enrollment

A total of 212 patients will be accrued over a 3 year period.

Outline

This is a randomized study.  Patients are stratified by age (less than 50 
versus at least 50) and by type of relapse/prior therapy.

Arm I:  Patients receive mitoxantrone/etoposide/cytarabine (MEC) intravenously
once daily for 5 days. 

Arm II:  Patients receive MEC intravenously once daily for 5 days plus PSC 833
treatment.  PSC 833 is administered intravenously for 120 hours beginning 4 
hours prior to first dose of mitoxantrone and etoposide.

Arms I and II:  Four to eight days after the last dose, a bone marrow aspirate 
and biopsy is performed.  Patients who have not achieved complete remission 
(CR) receive a second course of therapy.  A second bone marrow aspirate and 
biopsy is performed 4 to 8 days after the second course of therapy.  If 
patients do not achieve CR after 2 courses of treatment, they receive 
supportive care and are discontinued from the study.

Patients are followed every 3 months until relapse or death.

Greenberg PL, Lee SJ, Advani R, et al.: Mitoxantrone, etoposide, and cytarabine with or without valspodar in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome: a phase III trial (E2995). J Clin Oncol 22 (6): 1078-86, 2004.[PUBMED Abstract]

Greenberg P, Advani R, Tallman M, et al.: Treatment of refractory/relasped AML with PSC833 Plus mitoxantrone, etoposide, cytarabine (PSC-MEC) vs MEC: randomized phase III trial E2995. [Abstract] Blood 94: (10 suppl 1, pt 1): A-1703, 383a, 1999.

Paietta E, Goloubeva O, Neuberg D, et al.: A surrogate marker profile for PML/RAR alpha expressing acute promyelocytic leukemia and the association of immunophenotypic markers with morphologic and molecular subtypes. Cytometry B Clin Cytom 59B (1): 1-9, 2004.[PUBMED Abstract]

Paietta E, Goloubeva O, Bennett JM, et al.: A surrogate marker profile for acute promyelocytic leukemia (APL) and the association of immunophenotypic markers with morphologic and molecular subtypes of APL. [Abstract] Blood 100 (11 pt 2): A-4434, 2002.

Trial Contact Information

Trial Lead Organizations

Eastern Cooperative Oncology Group

Peter Greenberg, MD, Protocol chair		Ph: 650-725-8355; 800-756-9000 Email: peterg@stanford.edu

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