Phase III Randomized Study of Mitoxantrone/Etoposide/Cytarabine (MEC) versus MEC Plus PSC 833 (PSC MEC) in Patients with Recurrent or Refractory Acute Myelogenous Leukemia (AML)
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
|Phase III||Treatment||Completed||15 to 70||NCI||E-2995|
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.
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
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
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
A total of 212 patients will be accrued over a 3 year period.
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
Ph: 650-725-8355; 800-756-9000
Note: The purpose of most clinical trials listed in this database is to test new cancer treatments, or new methods of diagnosing, screening, or preventing cancer. Because all potentially harmful side effects are not known before a trial is conducted, dose and schedule modifications may be required for participants if they develop side effects from the treatment or test. The therapy or test described in this clinical trial is intended for use by clinical oncologists in carefully structured settings, and may not prove to be more effective than standard treatment. A responsible investigator associated with this clinical trial should be consulted before using this protocol.