Phase III Randomized Study of Induction Chemotherapy With or Without MDR-Modulation With PSC-833 (NSC # 648265, IND # 41121) Followed by Cytogenetic Risk-Adapted Intensification Therapy Followed by Immunotherapy With rIL-2 (NSC # 373364, IND # 1969) vs. Observation in Previously Untreated Patients With AML < 60 Years
Overview
- Phase
- Phase 3
- Intervention
- cytarabine
- Conditions
- Adult Acute Basophilic Leukemia
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 720
- Locations
- 1
- Primary Endpoint
- Disease-free survival
- Status
- Completed
- Last Updated
- 12 years ago
Overview
Brief Summary
Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. PSC 833 may increase the effectiveness of chemotherapy by making cancer cells more sensitive to the drugs. Combining chemotherapy with peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more cancer cells. Interleukin-2 may stimulate a person's white blood cells to kill cancer cells. This randomized phase III trial is studying giving combination chemotherapy together with PSC 833 followed by a peripheral stem cell transplant with or without interleukin-2 to see how well it works compared to combination chemotherapy alone followed by a peripheral stem cell transplant with or without interleukin-2 in treating patients with acute myeloid leukemia.
Detailed Description
PRIMARY OBJECTIVES: I. To determine whether the addition of PSC-833 (valspodar) to induction chemotherapy improves disease-free survival and overall survival for patients with acute myeloid leukemia (AML) \< 60 years. II. To determine whether post-consolidation immunotherapy with low-dose continuous/intermittent high-dose bolus subcutaneous recombinant interleukin-2 (rIL-2) (aldesleukin) improves disease-free survival and overall survival in patients with AML \< 60 years in first complete remission (CR). SECONDARY OBJECTIVES: I. To continue to evaluate the effectiveness of three courses of high-dose ARA-C (HiDAC) (cytarabine) as curative consolidation chemotherapy in patients with core binding factor (CBF) leukemias. II. To continue to establish the use of intensive post-remission chemotherapy with PSCT or a novel intensification sequence consisting of HiDAC/high-dose etoposide/G-CSF (filgrastim) followed by two cycles of HiDAC in patients in CR with unfavorable cytogenetics. III. To correlate the rate of relapse and toxicity with busulfan pharmacokinetics when busulfan and etoposide are used prior to autologous stem cell transplantation for AML patients in first CR. OUTLINE: This is a randomized, multicenter study. INDUCTION THERAPY: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive cytarabine IV continuously on days 1-7 and daunorubicin IV over 5-10 minutes followed by etoposide IV over 2 hours on days 1-3. Patients with 20% or greater bone marrow cellularity and greater than 5% leukemia blasts at the end of the first course receive a second course of cytarabine IV continuously on days 1-5 and daunorubicin IV over 5-10 minutes followed by etoposide IV over 2 hours on days 1 and 2. ARM II: Patients receive PSC 833 IV continuously on days 1-3 and cytarabine, daunorubicin, and etoposide as in arm I. Patients with 20% or greater bone marrow cellularity and greater than 5% leukemia blasts at the end of the first course receive a second course of PSC 833 IV continuously on days 1 and 2 and cytarabine, daunorubicin, and etoposide as in arm I. INTENSIFICATION THERAPY: Patients in complete remission receive intensification therapy. Therapy begins no earlier than 2 weeks and no later than 4 weeks after complete remission is attained. Patients are stratified according to cytogenetics (favorable \[t(8;21)(q22;q22) or inv(16)(p13;q22) or t(16;16)(p13;q22)\] vs unfavorable \[all other karyotypes\]). FAVORABLE: Patients receive high-dose cytarabine (HiDAC) IV over 3 hours every 12 hours on days 1, 3, and 5. Treatment repeats no earlier than 28 days after the prior course and no later than 14 days after hematopoietic recovery for two more courses. UNFAVORABLE: Patients are further divided into two groups based on ability to receive peripheral blood stem cell transplantation (PBSCT) (yes vs no). PBSCT GROUP: Patients receive etoposide IV continuously and HiDAC IV over 2 hours every 12 hours on days 1-4. Patients also receive filgrastim (G-CSF) subcutaneously (SC) daily beginning on day 14 and continuing until peripheral blood stem cell (PBSC) collection is completed. Patients who are not able to undergo PBSCT after HiDAC/etoposide continue treatment in the non-PBSCT group. At least 4 weeks after HiDAC/etoposide recovery, patients receive oral busulfan every 6 hours on days -7 to -4 and etoposide IV over 4 hours on day -3 prior to PBSCT. Patients receive autologous PBSC infusion on day 0. Patients also receive G-CSF SC beginning on day 0 and continuing until hematopoietic recovery. NON-PBSCT GROUP: Patients receive etoposide, HiDAC, and G-CSF as in the PBSCT group. After hematopoietic recovery, patients then receive HiDAC IV over 3 hours every 12 hours on days 1, 3, and 5. Treatment repeats no earlier than 28 days after prior course and no later than 14 days after hematopoietic recovery for one more course. IMMUNOTHERAPY: Patients are again randomized to 1 of 2 treatment arms. ARM I: Patients begin therapy no later than 120 days after the first day of the last course of HiDAC treatment OR day 0 of PBSCT. Patients receive low-dose interleukin-2 (IL-2) SC on days 1-14, 19-28, 33-42, 47-56, 61-70, and 75-90. In addition, patients receive high-dose IL-2 SC on days 15-17, 29-31, 43-45, 57-59, and 71-73. ARM II: Patients are observed and receive no further therapy. Patients are followed at 1 month, every 2 months for 2 years, every 6 months for 2 years, and then annually for 6 years. PROJECTED ACCRUAL: A total of 720 patients will be accrued for this study within 4 years.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Unequivocal histologic diagnosis of AML (\> 20% blasts in the bone marrow based on the World Health Organization \[WHO\] and/or French-American-British Cooperative group \[FAB\] classifications), excluding M3 (acute promyelocytic leukemia); patients with antecedent myelodysplasia are eligible for treatment on this trial only if there was no bone marrow biopsy showing myelodysplastic syndrome (MDS) \> 3 months prior to enrollment; patients with therapy-related MDS or therapy-related AML or a chronic myeloproliferative disorder are not eligible
- •No prior treatment for leukemia or myelodysplasia with four permissible exceptions:
- •Emergency leukapheresis
- •Emergency treatment for hyperleukocytosis with hydroxyurea
- •Cranial radiation therapy (RT) for central nervous system (CNS) leukostasis (one dose only)
- •Growth factor/cytokine support
Exclusion Criteria
- Not provided
Arms & Interventions
Induction Arm I
Patients receive cytarabine IV continuously on days 1-7 and daunorubicin IV over 5-10 minutes followed by etoposide IV over 2 hours on days 1-3. Patients with 20% or greater bone marrow cellularity and greater than 5% leukemia blasts at the end of the first course receive a second course of cytarabine IV continuously on days 1-5 and daunorubicin IV over 5-10 minutes followed by etoposide IV over 2 hours on days 1 and 2.
Intervention: cytarabine
Induction Arm I
Patients receive cytarabine IV continuously on days 1-7 and daunorubicin IV over 5-10 minutes followed by etoposide IV over 2 hours on days 1-3. Patients with 20% or greater bone marrow cellularity and greater than 5% leukemia blasts at the end of the first course receive a second course of cytarabine IV continuously on days 1-5 and daunorubicin IV over 5-10 minutes followed by etoposide IV over 2 hours on days 1 and 2.
Intervention: daunorubicin hydrochloride
Induction Arm I
Patients receive cytarabine IV continuously on days 1-7 and daunorubicin IV over 5-10 minutes followed by etoposide IV over 2 hours on days 1-3. Patients with 20% or greater bone marrow cellularity and greater than 5% leukemia blasts at the end of the first course receive a second course of cytarabine IV continuously on days 1-5 and daunorubicin IV over 5-10 minutes followed by etoposide IV over 2 hours on days 1 and 2.
Intervention: etoposide
Induction Arm I
Patients receive cytarabine IV continuously on days 1-7 and daunorubicin IV over 5-10 minutes followed by etoposide IV over 2 hours on days 1-3. Patients with 20% or greater bone marrow cellularity and greater than 5% leukemia blasts at the end of the first course receive a second course of cytarabine IV continuously on days 1-5 and daunorubicin IV over 5-10 minutes followed by etoposide IV over 2 hours on days 1 and 2.
Intervention: pharmacological study
Induction Arm II
Patients receive PSC 833 IV continuously on days 1-3 and cytarabine, daunorubicin, and etoposide as in arm I. Patients with 20% or greater bone marrow cellularity and greater than 5% leukemia blasts at the end of the first course receive a second course of PSC 833 IV continuously on days 1 and 2 and cytarabine, daunorubicin, and etoposide as in arm I.
Intervention: cytarabine
Induction Arm II
Patients receive PSC 833 IV continuously on days 1-3 and cytarabine, daunorubicin, and etoposide as in arm I. Patients with 20% or greater bone marrow cellularity and greater than 5% leukemia blasts at the end of the first course receive a second course of PSC 833 IV continuously on days 1 and 2 and cytarabine, daunorubicin, and etoposide as in arm I.
Intervention: daunorubicin hydrochloride
Induction Arm II
Patients receive PSC 833 IV continuously on days 1-3 and cytarabine, daunorubicin, and etoposide as in arm I. Patients with 20% or greater bone marrow cellularity and greater than 5% leukemia blasts at the end of the first course receive a second course of PSC 833 IV continuously on days 1 and 2 and cytarabine, daunorubicin, and etoposide as in arm I.
Intervention: etoposide
Induction Arm II
Patients receive PSC 833 IV continuously on days 1-3 and cytarabine, daunorubicin, and etoposide as in arm I. Patients with 20% or greater bone marrow cellularity and greater than 5% leukemia blasts at the end of the first course receive a second course of PSC 833 IV continuously on days 1 and 2 and cytarabine, daunorubicin, and etoposide as in arm I.
Intervention: valspodar
Induction Arm II
Patients receive PSC 833 IV continuously on days 1-3 and cytarabine, daunorubicin, and etoposide as in arm I. Patients with 20% or greater bone marrow cellularity and greater than 5% leukemia blasts at the end of the first course receive a second course of PSC 833 IV continuously on days 1 and 2 and cytarabine, daunorubicin, and etoposide as in arm I.
Intervention: pharmacological study
Intensification Favorable
Patients receive HiDAC IV over 3 hours every 12 hours on days 1, 3, and 5. Treatment repeats no earlier than 28 days after the prior course and no later than 14 days after hematopoietic recovery for two more courses.
Intervention: cytarabine
Intensification Favorable
Patients receive HiDAC IV over 3 hours every 12 hours on days 1, 3, and 5. Treatment repeats no earlier than 28 days after the prior course and no later than 14 days after hematopoietic recovery for two more courses.
Intervention: pharmacological study
Intensification Unfavorable PBSCT Group
Patients receive etoposide IV continuously and HiDAC IV over 2 hours every 12 hours on days 1-4. Patients also receive G-CSF SC daily beginning on day 14 and continuing until PBSC collection is completed. Patients who are not able to undergo PBSCT after HiDAC/etoposide continue treatment in the non-PBSCT group. At least 4 weeks after HiDAC/etoposide recovery, patients receive oral busulfan every 6 hours on days -7 to -4 and etoposide IV over 4 hours on day -3 prior to PBSCT. Patients receive autologous PBSC infusion on day 0. Patients also receive G-CSF SC beginning on day 0 and continuing until hematopoietic recovery.
Intervention: cytarabine
Intensification Unfavorable PBSCT Group
Patients receive etoposide IV continuously and HiDAC IV over 2 hours every 12 hours on days 1-4. Patients also receive G-CSF SC daily beginning on day 14 and continuing until PBSC collection is completed. Patients who are not able to undergo PBSCT after HiDAC/etoposide continue treatment in the non-PBSCT group. At least 4 weeks after HiDAC/etoposide recovery, patients receive oral busulfan every 6 hours on days -7 to -4 and etoposide IV over 4 hours on day -3 prior to PBSCT. Patients receive autologous PBSC infusion on day 0. Patients also receive G-CSF SC beginning on day 0 and continuing until hematopoietic recovery.
Intervention: etoposide
Intensification Unfavorable PBSCT Group
Patients receive etoposide IV continuously and HiDAC IV over 2 hours every 12 hours on days 1-4. Patients also receive G-CSF SC daily beginning on day 14 and continuing until PBSC collection is completed. Patients who are not able to undergo PBSCT after HiDAC/etoposide continue treatment in the non-PBSCT group. At least 4 weeks after HiDAC/etoposide recovery, patients receive oral busulfan every 6 hours on days -7 to -4 and etoposide IV over 4 hours on day -3 prior to PBSCT. Patients receive autologous PBSC infusion on day 0. Patients also receive G-CSF SC beginning on day 0 and continuing until hematopoietic recovery.
Intervention: filgrastim
Intensification Unfavorable PBSCT Group
Patients receive etoposide IV continuously and HiDAC IV over 2 hours every 12 hours on days 1-4. Patients also receive G-CSF SC daily beginning on day 14 and continuing until PBSC collection is completed. Patients who are not able to undergo PBSCT after HiDAC/etoposide continue treatment in the non-PBSCT group. At least 4 weeks after HiDAC/etoposide recovery, patients receive oral busulfan every 6 hours on days -7 to -4 and etoposide IV over 4 hours on day -3 prior to PBSCT. Patients receive autologous PBSC infusion on day 0. Patients also receive G-CSF SC beginning on day 0 and continuing until hematopoietic recovery.
Intervention: busulfan
Intensification Unfavorable PBSCT Group
Patients receive etoposide IV continuously and HiDAC IV over 2 hours every 12 hours on days 1-4. Patients also receive G-CSF SC daily beginning on day 14 and continuing until PBSC collection is completed. Patients who are not able to undergo PBSCT after HiDAC/etoposide continue treatment in the non-PBSCT group. At least 4 weeks after HiDAC/etoposide recovery, patients receive oral busulfan every 6 hours on days -7 to -4 and etoposide IV over 4 hours on day -3 prior to PBSCT. Patients receive autologous PBSC infusion on day 0. Patients also receive G-CSF SC beginning on day 0 and continuing until hematopoietic recovery.
Intervention: autologous hematopoietic stem cell transplantation
Intensification Unfavorable PBSCT Group
Patients receive etoposide IV continuously and HiDAC IV over 2 hours every 12 hours on days 1-4. Patients also receive G-CSF SC daily beginning on day 14 and continuing until PBSC collection is completed. Patients who are not able to undergo PBSCT after HiDAC/etoposide continue treatment in the non-PBSCT group. At least 4 weeks after HiDAC/etoposide recovery, patients receive oral busulfan every 6 hours on days -7 to -4 and etoposide IV over 4 hours on day -3 prior to PBSCT. Patients receive autologous PBSC infusion on day 0. Patients also receive G-CSF SC beginning on day 0 and continuing until hematopoietic recovery.
Intervention: peripheral blood stem cell transplantation
Intensification Unfavorable PBSCT Group
Patients receive etoposide IV continuously and HiDAC IV over 2 hours every 12 hours on days 1-4. Patients also receive G-CSF SC daily beginning on day 14 and continuing until PBSC collection is completed. Patients who are not able to undergo PBSCT after HiDAC/etoposide continue treatment in the non-PBSCT group. At least 4 weeks after HiDAC/etoposide recovery, patients receive oral busulfan every 6 hours on days -7 to -4 and etoposide IV over 4 hours on day -3 prior to PBSCT. Patients receive autologous PBSC infusion on day 0. Patients also receive G-CSF SC beginning on day 0 and continuing until hematopoietic recovery.
Intervention: pharmacological study
Intensification Unfavorable Non-PBSCT Group
Patients receive etoposide, HiDAC, and G-CSF as in the PBSCT group. After hematopoietic recovery, patients then receive HiDAC IV over 3 hours every 12 hours on days 1, 3, and 5. Treatment repeats no earlier than 28 days after prior course and no later than 14 days after hematopoietic recovery for one more course.
Intervention: cytarabine
Intensification Unfavorable Non-PBSCT Group
Patients receive etoposide, HiDAC, and G-CSF as in the PBSCT group. After hematopoietic recovery, patients then receive HiDAC IV over 3 hours every 12 hours on days 1, 3, and 5. Treatment repeats no earlier than 28 days after prior course and no later than 14 days after hematopoietic recovery for one more course.
Intervention: etoposide
Intensification Unfavorable Non-PBSCT Group
Patients receive etoposide, HiDAC, and G-CSF as in the PBSCT group. After hematopoietic recovery, patients then receive HiDAC IV over 3 hours every 12 hours on days 1, 3, and 5. Treatment repeats no earlier than 28 days after prior course and no later than 14 days after hematopoietic recovery for one more course.
Intervention: filgrastim
Intensification Unfavorable Non-PBSCT Group
Patients receive etoposide, HiDAC, and G-CSF as in the PBSCT group. After hematopoietic recovery, patients then receive HiDAC IV over 3 hours every 12 hours on days 1, 3, and 5. Treatment repeats no earlier than 28 days after prior course and no later than 14 days after hematopoietic recovery for one more course.
Intervention: pharmacological study
Immunotherapy Arm I
Patients begin therapy no later than 120 days after the first day of the last course of HiDAC treatment OR day 0 of PBSCT. Patients receive low-dose IL-2 SC on days 1-14, 19-28, 33-42, 47-56, 61-70, and 75-90. In addition, patients receive high-dose IL-2 SC on days 15-17, 29-31, 43-45, 57-59, and 71-73.
Intervention: aldesleukin
Immunotherapy Arm I
Patients begin therapy no later than 120 days after the first day of the last course of HiDAC treatment OR day 0 of PBSCT. Patients receive low-dose IL-2 SC on days 1-14, 19-28, 33-42, 47-56, 61-70, and 75-90. In addition, patients receive high-dose IL-2 SC on days 15-17, 29-31, 43-45, 57-59, and 71-73.
Intervention: pharmacological study
Immunotherapy Arm II
Patients are observed and receive no further therapy.
Intervention: clinical observation
Immunotherapy Arm II
Patients are observed and receive no further therapy.
Intervention: pharmacological study
Outcomes
Primary Outcomes
Disease-free survival
Time Frame: Up to 10 years
An unstratified logrank test for the induction treatment comparison and a stratified logrank test for the post-remission treatment comparison will be the primary statistical methods used for treatment comparisons.
Overall survival
Time Frame: Up to 10 years
An unstratified logrank test for the induction treatment comparison and a stratified logrank test for the post-remission treatment comparison will be the primary statistical methods used for treatment comparisons.
Secondary Outcomes
- Estimates of disease-free survival curves(Up to 10 years)
- Estimates of overall survival curves(Up to 10 years)
- Toxicities and adverse events assessed using National Cancer Institute (NCI) Common Toxicity Criteria (CTC)(Up to 10 years)