Combination Chemotherapy With or Without PSC 833, Peripheral Stem Cell Transplantation, and/or Interleukin-2 in Treating Patients With Acute Myeloid Leukemia

National Cancer Institute (NCI)

Status and phase

Completed

Phase 3

Conditions

Childhood Acute Erythroleukemia (M6)

Adult Acute Basophilic Leukemia

Untreated Adult Acute Myeloid Leukemia

Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)

Adult Pure Erythroid Leukemia (M6b)

Adult Acute Eosinophilic Leukemia

Childhood Myelodysplastic Syndromes

Adult Acute Monoblastic Leukemia (M5a)

Adult Acute Myelomonocytic Leukemia (M4)

Childhood Acute Minimally Differentiated Myeloid Leukemia (M0)

Adult Acute Myeloblastic Leukemia Without Maturation (M1)

Adult Acute Minimally Differentiated Myeloid Leukemia (M0)

Adult Acute Monocytic Leukemia (M5b)

Childhood Acute Basophilic Leukemia

Adult Acute Myeloid Leukemia With Del(5q)

Childhood Acute Monoblastic Leukemia and Acute Monocytic Leukemia (M5)

Adult Acute Megakaryoblastic Leukemia (M7)

Adult Erythroleukemia (M6a)

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities

de Novo Myelodysplastic Syndromes

Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)

Childhood Acute Monocytic Leukemia (M5b)

Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

Adult Acute Erythroid Leukemia (M6)

Childhood Acute Monoblastic Leukemia (M5a)

Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)

Childhood Acute Megakaryocytic Leukemia (M7)

Adult Acute Myeloblastic Leukemia With Maturation (M2)

Childhood Acute Eosinophilic Leukemia

Adult Acute Monoblastic Leukemia and Acute Monocytic Leukemia (M5)

Childhood Acute Myeloblastic Leukemia Without Maturation (M1)

Childhood Acute Myelomonocytic Leukemia (M4)

Childhood Acute Myeloblastic Leukemia With Maturation (M2)

Treatments

Procedure: peripheral blood stem cell transplantation

Drug: cytarabine

Drug: daunorubicin hydrochloride

Drug: busulfan

Biological: aldesleukin

Drug: valspodar

Other: pharmacological study

Procedure: autologous hematopoietic stem cell transplantation

Drug: etoposide

Biological: filgrastim

Other: clinical observation

Study type

Interventional

Funder types

NIH

Identifiers

NCT00006363

CALGB-19808

U10CA031946 (U.S. NIH Grant/Contract)

NCI-2012-02824

Details and patient eligibility

About

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.

Full 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.

Enrollment

720 patients

Sex

All

Ages

15 to 59 years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion 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

Trial design

Primary purpose

Treatment

Allocation

Randomized

Interventional model

Parallel Assignment

Masking

None (Open label)

720 participants in 7 patient groups

Induction Arm I

Experimental group

Description:

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.

Treatment:

Drug: etoposide

Other: pharmacological study

Drug: daunorubicin hydrochloride

Drug: cytarabine

Induction Arm II

Experimental group

Description:

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.

Treatment:

Drug: etoposide

Other: pharmacological study

Drug: valspodar

Drug: daunorubicin hydrochloride

Drug: cytarabine

Intensification Favorable

Experimental group

Description:

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.

Treatment:

Other: pharmacological study

Drug: cytarabine

Intensification Unfavorable PBSCT Group

Experimental group

Description:

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.

Treatment:

Biological: filgrastim

Drug: etoposide

Other: pharmacological study

Drug: busulfan

Procedure: peripheral blood stem cell transplantation

Procedure: autologous hematopoietic stem cell transplantation

Drug: cytarabine

Intensification Unfavorable Non-PBSCT Group

Experimental group

Description:

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.

Treatment:

Biological: filgrastim

Drug: etoposide

Other: pharmacological study

Drug: cytarabine

Immunotherapy Arm I

Experimental group

Description:

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.

Treatment:

Other: pharmacological study

Biological: aldesleukin

Immunotherapy Arm II

Active Comparator group

Description:

Patients are observed and receive no further therapy.

Treatment:

Other: clinical observation

Other: pharmacological study