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

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ClinicalTrials.gov Identifier: NCT00006363

Recruitment Status : Completed

First Posted : January 27, 2003

Last Update Posted : June 4, 2013

View this study on Beta.ClinicalTrials.gov

Sponsor:

Information provided by (Responsible Party):

National Cancer Institute (NCI)

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Adult Acute Basophilic Leukemia Adult Acute Eosinophilic Leukemia Adult Acute Erythroid Leukemia (M6) Adult Acute Megakaryoblastic Leukemia (M7) Adult Acute Minimally Differentiated Myeloid Leukemia (M0) Adult Acute Monoblastic Leukemia (M5a) Adult Acute Monoblastic Leukemia and Acute Monocytic Leukemia (M5) Adult Acute Monocytic Leukemia (M5b) Adult Acute Myeloblastic Leukemia With Maturation (M2) Adult Acute Myeloblastic Leukemia Without Maturation (M1) Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities Adult Acute Myeloid Leukemia With Del(5q) Adult Acute Myeloid Leukemia With Inv(16)(p13;q22) Adult Acute Myeloid Leukemia With t(16;16)(p13;q22) Adult Acute Myeloid Leukemia With t(8;21)(q22;q22) Adult Acute Myelomonocytic Leukemia (M4) Adult Erythroleukemia (M6a) Adult Pure Erythroid Leukemia (M6b) Childhood Acute Basophilic Leukemia Childhood Acute Eosinophilic Leukemia Childhood Acute Erythroleukemia (M6) Childhood Acute Megakaryocytic Leukemia (M7) Childhood Acute Minimally Differentiated Myeloid Leukemia (M0) Childhood Acute Monoblastic Leukemia (M5a) Childhood Acute Monoblastic Leukemia and Acute Monocytic Leukemia (M5) Childhood Acute Monocytic Leukemia (M5b) Childhood Acute Myeloblastic Leukemia With Maturation (M2) Childhood Acute Myeloblastic Leukemia Without Maturation (M1) Childhood Acute Myelomonocytic Leukemia (M4) Childhood Myelodysplastic Syndromes de Novo Myelodysplastic Syndromes Untreated Adult Acute Myeloid Leukemia Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies	Drug: cytarabine Drug: daunorubicin hydrochloride Drug: etoposide Drug: valspodar Biological: filgrastim Drug: busulfan Procedure: autologous hematopoietic stem cell transplantation Procedure: peripheral blood stem cell transplantation Biological: aldesleukin Other: clinical observation Other: pharmacological study	Phase 3

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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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	720 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	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
Study Start Date :	November 2000
Actual Primary Completion Date :	June 2005

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Familial acute myeloid leukemia with mutated CEBPA Cytogenetically normal acute myeloid leukemia Core binding factor acute myeloid leukemia

MedlinePlus related topics: Leukemia

Genetic and Rare Diseases Information Center resources: Myelodysplastic Syndromes Myeloid Leukemia Acute Myeloid Leukemia Acute Non Lymphoblastic Leukemia Acute Graft Versus Host Disease Acute Monoblastic Leukemia Acute Myelomonocytic Leukemia Acute Erythroid Leukemia Di Guglielmo's Syndrome Acute Megakaryoblastic Leukemia Acute Myeloblastic Leukemia Without Maturation Acute Myeloblastic Leukemia With Maturation Chronic Myelomonocytic Leukemia Chronic Graft Versus Host Disease Hypereosinophilic Syndrome Chronic Myeloproliferative Disorders Myelodysplastic/myeloproliferative Disease

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Experimental: 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.	Drug: cytarabine Given IV Other Names: ARA-C arabinofuranosylcytosine arabinosylcytosine Cytosar-U cytosine arabinoside Drug: daunorubicin hydrochloride Given IV Other Names: Cerubidin Cerubidine daunomycin hydrochloride daunorubicin RP-13057 Drug: etoposide Given IV Other Names: EPEG VP-16 VP-16-213 Other: pharmacological study Correlative studies Other Name: pharmacological studies
Experimental: 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.	Drug: cytarabine Given IV Other Names: ARA-C arabinofuranosylcytosine arabinosylcytosine Cytosar-U cytosine arabinoside Drug: daunorubicin hydrochloride Given IV Other Names: Cerubidin Cerubidine daunomycin hydrochloride daunorubicin RP-13057 Drug: etoposide Given IV Other Names: EPEG VP-16 VP-16-213 Drug: valspodar Given IV Other Names: Amdray PSC 833 Other: pharmacological study Correlative studies Other Name: pharmacological studies
Experimental: 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.	Drug: cytarabine Given IV Other Names: ARA-C arabinofuranosylcytosine arabinosylcytosine Cytosar-U cytosine arabinoside Other: pharmacological study Correlative studies Other Name: pharmacological studies
Experimental: 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.	Drug: cytarabine Given IV Other Names: ARA-C arabinofuranosylcytosine arabinosylcytosine Cytosar-U cytosine arabinoside Drug: etoposide Given IV Other Names: EPEG VP-16 VP-16-213 Biological: filgrastim Given SC Other Names: G-CSF Neupogen Drug: busulfan Given orally Other Names: BSF BU Misulfan Mitosan Myeloleukon Procedure: autologous hematopoietic stem cell transplantation Undergo autologous PBSCT Procedure: peripheral blood stem cell transplantation Undergo autologous PBSCT Other Names: PBPC transplantation PBSC transplantation peripheral blood progenitor cell transplantation transplantation, peripheral blood stem cell Other: pharmacological study Correlative studies Other Name: pharmacological studies
Experimental: 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.	Drug: cytarabine Given IV Other Names: ARA-C arabinofuranosylcytosine arabinosylcytosine Cytosar-U cytosine arabinoside Drug: etoposide Given IV Other Names: EPEG VP-16 VP-16-213 Biological: filgrastim Given SC Other Names: G-CSF Neupogen Other: pharmacological study Correlative studies Other Name: pharmacological studies
Experimental: 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.	Biological: aldesleukin Given SC Other Names: IL-2 Proleukin recombinant human interleukin-2 recombinant interleukin-2 Other: pharmacological study Correlative studies Other Name: pharmacological studies
Active Comparator: Immunotherapy Arm II Patients are observed and receive no further therapy.	Other: clinical observation Undergo clinical observation Other Name: observation Other: pharmacological study Correlative studies Other Name: pharmacological studies

Outcome Measures

Primary Outcome Measures :

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 Outcome Measures :

Estimates of disease-free survival curves [ Time Frame: Up to 10 years ]
Estimates of overall survival curves [ Time Frame: Up to 10 years ]
Toxicities and adverse events assessed using National Cancer Institute (NCI) Common Toxicity Criteria (CTC) [ Time Frame: Up to 10 years ]
Will be tabulated.

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:	15 Years to 59 Years (Child, Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00006363

Locations

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United States, Illinois
Cancer and Leukemia Group B
Chicago, Illinois, United States, 60606

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

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Principal Investigator:	Jonathan Kolitz	Cancer and Leukemia Group B

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Walker CJ, Kohlschmidt J, Eisfeld AK, Mrozek K, Liyanarachchi S, Song C, Nicolet D, Blachly JS, Bill M, Papaioannou D, Oakes CC, Giacopelli B, Genutis LK, Maharry SE, Orwick S, Archer KJ, Powell BL, Kolitz JE, Uy GL, Wang ES, Carroll AJ, Stone RM, Byrd JC, de la Chapelle A, Bloomfield CD. Genetic Characterization and Prognostic Relevance of Acquired Uniparental Disomies in Cytogenetically Normal Acute Myeloid Leukemia. Clin Cancer Res. 2019 Nov 1;25(21):6524-6531. doi: 10.1158/1078-0432.CCR-19-0725. Epub 2019 Aug 2.

Kolitz JE, George SL, Marcucci G, Vij R, Powell BL, Allen SL, DeAngelo DJ, Shea TC, Stock W, Baer MR, Hars V, Maharry K, Hoke E, Vardiman JW, Bloomfield CD, Larson RA; Cancer and Leukemia Group B. P-glycoprotein inhibition using valspodar (PSC-833) does not improve outcomes for patients younger than age 60 years with newly diagnosed acute myeloid leukemia: Cancer and Leukemia Group B study 19808. Blood. 2010 Sep 2;116(9):1413-21. doi: 10.1182/blood-2009-07-229492. Epub 2010 Jun 3.

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Responsible Party:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00006363
Other Study ID Numbers:	NCI-2012-02824 CALGB-19808 U10CA031946 ( U.S. NIH Grant/Contract )
First Posted:	January 27, 2003 Key Record Dates
Last Update Posted:	June 4, 2013
Last Verified:	June 2013

Additional relevant MeSH terms:

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Leukemia Leukemia, Myeloid Leukemia, Myeloid, Acute Preleukemia Leukemia, Myelomonocytic, Acute Leukemia, Myelomonocytic, Chronic Leukemia, Monocytic, Acute Leukemia, Megakaryoblastic, Acute Leukemia, Erythroblastic, Acute Leukemia, Basophilic, Acute Leukemia, Eosinophilic, Acute Myelodysplastic Syndromes Hypereosinophilic Syndrome Syndrome Disease	Pathologic Processes Neoplasms by Histologic Type Neoplasms Bone Marrow Diseases Hematologic Diseases Precancerous Conditions Myelodysplastic-Myeloproliferative Diseases Eosinophilia Leukocyte Disorders Myeloproliferative Disorders Cytarabine Aldesleukin Etoposide Daunorubicin Etoposide phosphate

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