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

Sponsor:	Cancer and Leukemia Group B
Collaborator:	National Cancer Institute (NCI)
Information provided by:	Cancer and Leukemia Group B
ClinicalTrials.gov Identifier:	NCT00006363

Purpose

RATIONALE: 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.

PURPOSE: 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	Intervention	Phase
Leukemia	Biological: IL-2 Biological: G-CSF Drug: busulfan Drug: ara-C Drug: daunorubicin hydrochloride Drug: etoposide Drug: PSC-833 (DISCON'T 8/2003)	Phase III

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: 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

Resource links provided by NLM:

MedlinePlus related topics: Acute Myeloid Leukemia Cancer Leukemia

Drug Information available for: Busulfan Cytarabine hydrochloride Daunorubicin Daunorubicin hydrochloride Etoposide Aldesleukin Etoposide phosphate Filgrastim Sdz psc 833 Granulocyte colony-stimulating factor Cytarabine

U.S. FDA Resources

Further study details as provided by Cancer and Leukemia Group B:

Primary Outcome Measures:

Disease free survival [ Time Frame: 3 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

HiDAC Therapy Effectiveness [ Time Frame: 6 months ] [ Designated as safety issue: No ]
Assessment of 3 courses of HiDAC therapy inpatients with favorable cytogenetics
PSCT and Etoposide/G-CSF +HiDAC Effectiveness [ Time Frame: 6 months ] [ Designated as safety issue: No ]
Post remission Tx assessment for pts with unfavorable cytogenetics
Relapse/Toxicity of Busulfan + etoposide Tx [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
Comparison of toxicity of bisulfan used with etoposide and rate of relapse after 1st CR and prior to PSCT

Enrollment:	734
Study Start Date:	November 2000
Estimated Study Completion Date:	April 2016
Primary Completion Date:	March 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Active Comparator: ADE Induction Pta are randomized to Induction tx, then treated post remission based on cytogenetics then randomized to either observation or immunotherapy	Biological: IL-2 1,000,000 IU/sq m sub Q injection days 1-14, 19-28, 33-42, 47-56, 61-70, & 75-90 12,000,000 IU/sq m sub Q injection on Days 15-17, 29-31, 43-45, 57-59, & 71-73 followed by 15,000,000 IU/sq m sub Q in the absence of Grade 3-5 toxicities Other Name: aldesleukin Biological: G-CSF 10 ug/kg/d subQ injection Day 14 until PBSC collection is completed or WBC>50,000/uL during collection and 5 ug/kg/day subQ injection Day 0 until ANC > or = 1500 uL for 2 days or > or = 5000 uL for 1 day during transplant for pts with unfavorable cytogenetics Other Name: filgrastim Drug: busulfan 1 mg/kg PO (OR 0.8mg/kg IV infusion over 2 hrs) q 6 hrs x 16 doses Days -7 through -4 Drug: ara-C 100 mg/sq m/day CIVI days 1-7 (hrs 0-168 ADE & hrs 2-170 ADEP)remission 1 100mg/sq m/day CIVI days 1-5 (hrs 0-120 ADE & 2-122 ADEP) remission 2 Intensification: fav cytogen: 3 g/sq m IV over 3 hrs q 12 hrs days 1, 3, & 5 for 3 cycles; unfav cytogen: 2 g/sq m IV over 2 hrs q 12 hrs x 8 doses days 1-4; no PSCT: one cycle as per fav cytogen then 2 cycles as per unfav cytogen Other Name: cytarabine Drug: daunorubicin hydrochloride ADE: 90mg/sq m IV bolus days 1,2,& 3 1st remission, and days 1 & 2 2nd remission ADEP: 40mg/sq m IV bolus days 1,2,& 3 1st remission and days 1 & 2 2nd remission Drug: etoposide ADE: 100mg/sq m IV infusion over 2 hrs days 1,2, & 3 remission 1 and days 1 & 2 remission 2 ADEP: 40mg/sq m IV over 2 hrs days 1,2, & 3 remission 1 and days 1 & 2 remission 2
Experimental: ADEP Induction (DISCON'T 8/2003) Addition of cyclosporine analog PSC-833 to standard tx in remission induction DISCONTINUED ON AUGUST 11, 2003 DUE TO UNAVAILABILITY OF PSC-833	Biological: IL-2 1,000,000 IU/sq m sub Q injection days 1-14, 19-28, 33-42, 47-56, 61-70, & 75-90 12,000,000 IU/sq m sub Q injection on Days 15-17, 29-31, 43-45, 57-59, & 71-73 followed by 15,000,000 IU/sq m sub Q in the absence of Grade 3-5 toxicities Other Name: aldesleukin Biological: G-CSF 10 ug/kg/d subQ injection Day 14 until PBSC collection is completed or WBC>50,000/uL during collection and 5 ug/kg/day subQ injection Day 0 until ANC > or = 1500 uL for 2 days or > or = 5000 uL for 1 day during transplant for pts with unfavorable cytogenetics Other Name: filgrastim Drug: busulfan 1 mg/kg PO (OR 0.8mg/kg IV infusion over 2 hrs) q 6 hrs x 16 doses Days -7 through -4 Drug: ara-C 100 mg/sq m/day CIVI days 1-7 (hrs 0-168 ADE & hrs 2-170 ADEP)remission 1 100mg/sq m/day CIVI days 1-5 (hrs 0-120 ADE & 2-122 ADEP) remission 2 Intensification: fav cytogen: 3 g/sq m IV over 3 hrs q 12 hrs days 1, 3, & 5 for 3 cycles; unfav cytogen: 2 g/sq m IV over 2 hrs q 12 hrs x 8 doses days 1-4; no PSCT: one cycle as per fav cytogen then 2 cycles as per unfav cytogen Other Name: cytarabine Drug: daunorubicin hydrochloride ADE: 90mg/sq m IV bolus days 1,2,& 3 1st remission, and days 1 & 2 2nd remission ADEP: 40mg/sq m IV bolus days 1,2,& 3 1st remission and days 1 & 2 2nd remission Drug: etoposide ADE: 100mg/sq m IV infusion over 2 hrs days 1,2, & 3 remission 1 and days 1 & 2 remission 2 ADEP: 40mg/sq m IV over 2 hrs days 1,2, & 3 remission 1 and days 1 & 2 remission 2 Drug: PSC-833 (DISCON'T 8/2003) Loading dose of 2.8mg/kg IV over 2 hours for remission 1 and 2 then: 10 mg/kg/day CIVI days 1-3 beginning at hour 2 remission 1 10mg/kg/day CIVI days 1-2 beginning hr 2 remission 2

Arms

Assigned Interventions

Active Comparator: ADE Induction

Pta are randomized to Induction tx, then treated post remission based on cytogenetics then randomized to either observation or immunotherapy

Biological: IL-2

1,000,000 IU/sq m sub Q injection days 1-14, 19-28, 33-42, 47-56, 61-70, & 75-90 12,000,000 IU/sq m sub Q injection on Days 15-17, 29-31, 43-45, 57-59, & 71-73 followed by 15,000,000 IU/sq m sub Q in the absence of Grade 3-5 toxicities

Other Name: aldesleukin

Biological: G-CSF

10 ug/kg/d subQ injection Day 14 until PBSC collection is completed or WBC>50,000/uL during collection and 5 ug/kg/day subQ injection Day 0 until ANC > or = 1500 uL for 2 days or > or = 5000 uL for 1 day during transplant for pts with unfavorable cytogenetics

Other Name: filgrastim

Drug: busulfan

1 mg/kg PO (OR 0.8mg/kg IV infusion over 2 hrs) q 6 hrs x 16 doses Days -7 through -4

Drug: ara-C

100 mg/sq m/day CIVI days 1-7 (hrs 0-168 ADE & hrs 2-170 ADEP)remission 1 100mg/sq m/day CIVI days 1-5 (hrs 0-120 ADE & 2-122 ADEP) remission 2 Intensification: fav cytogen: 3 g/sq m IV over 3 hrs q 12 hrs days 1, 3, & 5 for 3 cycles; unfav cytogen: 2 g/sq m IV over 2 hrs q 12 hrs x 8 doses days 1-4; no PSCT: one cycle as per fav cytogen then 2 cycles as per unfav cytogen

Other Name: cytarabine

Drug: daunorubicin hydrochloride

ADE: 90mg/sq m IV bolus days 1,2,& 3 1st remission, and days 1 & 2 2nd remission ADEP: 40mg/sq m IV bolus days 1,2,& 3 1st remission and days 1 & 2 2nd remission

Drug: etoposide

ADE: 100mg/sq m IV infusion over 2 hrs days 1,2, & 3 remission 1 and days 1 & 2 remission 2 ADEP: 40mg/sq m IV over 2 hrs days 1,2, & 3 remission 1 and days 1 & 2 remission 2

Experimental: ADEP Induction (DISCON'T 8/2003)

Addition of cyclosporine analog PSC-833 to standard tx in remission induction DISCONTINUED ON AUGUST 11, 2003 DUE TO UNAVAILABILITY OF PSC-833

Biological: IL-2

1,000,000 IU/sq m sub Q injection days 1-14, 19-28, 33-42, 47-56, 61-70, & 75-90 12,000,000 IU/sq m sub Q injection on Days 15-17, 29-31, 43-45, 57-59, & 71-73 followed by 15,000,000 IU/sq m sub Q in the absence of Grade 3-5 toxicities

Other Name: aldesleukin

Biological: G-CSF

10 ug/kg/d subQ injection Day 14 until PBSC collection is completed or WBC>50,000/uL during collection and 5 ug/kg/day subQ injection Day 0 until ANC > or = 1500 uL for 2 days or > or = 5000 uL for 1 day during transplant for pts with unfavorable cytogenetics

Other Name: filgrastim

Drug: busulfan

1 mg/kg PO (OR 0.8mg/kg IV infusion over 2 hrs) q 6 hrs x 16 doses Days -7 through -4

Drug: ara-C

100 mg/sq m/day CIVI days 1-7 (hrs 0-168 ADE & hrs 2-170 ADEP)remission 1 100mg/sq m/day CIVI days 1-5 (hrs 0-120 ADE & 2-122 ADEP) remission 2 Intensification: fav cytogen: 3 g/sq m IV over 3 hrs q 12 hrs days 1, 3, & 5 for 3 cycles; unfav cytogen: 2 g/sq m IV over 2 hrs q 12 hrs x 8 doses days 1-4; no PSCT: one cycle as per fav cytogen then 2 cycles as per unfav cytogen

Other Name: cytarabine

Drug: daunorubicin hydrochloride

ADE: 90mg/sq m IV bolus days 1,2,& 3 1st remission, and days 1 & 2 2nd remission ADEP: 40mg/sq m IV bolus days 1,2,& 3 1st remission and days 1 & 2 2nd remission

Drug: etoposide

ADE: 100mg/sq m IV infusion over 2 hrs days 1,2, & 3 remission 1 and days 1 & 2 remission 2 ADEP: 40mg/sq m IV over 2 hrs days 1,2, & 3 remission 1 and days 1 & 2 remission 2

Drug: PSC-833 (DISCON'T 8/2003)

Loading dose of 2.8mg/kg IV over 2 hours for remission 1 and 2 then:

10 mg/kg/day CIVI days 1-3 beginning at hour 2 remission 1 10mg/kg/day CIVI days 1-2 beginning hr 2 remission 2

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Eligibility

Ages Eligible for Study:	15 Years to 59 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

DISEASE CHARACTERISTICS:

Histologically confirmed acute myeloid leukemia (AML) with more than 20% blasts in bone marrow by WHO and/or FAB classifications
- Antecedent myelodysplasia allowed if there was no bone marrow biopsy showing myelodysplastic syndromes over the previous 3 months
- No acute promyelocytic leukemia (M3)
- No therapy-related myelodysplastic syndromes or AML
- No chronic myeloproliferative disorder
Must also be enrolled on CALGB 9665 unless inaspirable and mandatory leukemic cells cannot be obtained from the blood

PATIENT CHARACTERISTICS:

Age:

15 to 59

Performance status:

Not specified

Life expectancy:

Not specified

Hematopoietic:

Not specified

Hepatic:

Not specified

Renal:

Not specified

Other:

Not pregnant or nursing
Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

Prior emergency leukapheresis allowed
Prior growth factor/cytokine support allowed
No other prior biologic therapy
Other concurrent myeloid growth factors allowed only if prognostic factors predictive of clinical deterioration are present such as the following:
- Pneumonia
- Hypotension
- Multiorgan dysfunction (sepsis syndrome)
- Fungal infection

Chemotherapy:

Prior emergency treatment for hyperleukocytosis with hydroxyurea allowed
No other prior chemotherapy
No other concurrent chemotherapy

Endocrine therapy:

No prior endocrine therapy
No concurrent hormonal therapy other than steroids for adrenal failure or septic shock or hormones for conditions not related to disease (e.g., insulin for diabetes or estrogens or progestins for gynecologic indications)

Radiotherapy:

One dose of prior cranial radiotherapy for CNS leukostasis allowed
No other prior radiotherapy
No concurrent radiotherapy

Surgery:

Not specified

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00006363

Show 79 Study Locations

Sponsors and Collaborators

Cancer and Leukemia Group B

National Cancer Institute (NCI)

Investigators

Study Chair:

Jonathan E. Kolitz, MD

Don Monti Comprehensive Cancer Center at North Shore University Hospital

More Information

Additional Information:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

Publications:

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. P-glycoprotein inhibition using valspodar (PSC-833) does not improve outcomes for patients under age 60 years with newly diagnosed acute myeloid leukemia: Cancer and Leukemia Group B study 19808. Blood. 2010 Jun 3; [Epub ahead of print]

Attar EC, Maharry K, Mrózek K, et al.: Increased expression of macrophage migration inhibitory factor (MIF) receptor CD74 is associated with inferior outcome in younger patients (Pts) with cytogenetically normal acute myeloid leukemia (CN-AML): a Cancer and Leukemia Group B (CALGB) study. [Abstract] Blood 114 (22): A-1616, 2009.

Kolitz JE, Hars V, DeAngelo DJ, et al.: Phase III trial of immunotherapy with recombinant interleukin-2 (rIL-2) versus observation in patients < 60 years with acute myeloid leukemia (AML) in first remission (CR1): preliminary results from Cancer and Leukemia Group B (CALGB) 19808. [Abstract] Blood 110 (11): A-157, 2007.

Radmacher MD, Marcucci G, Paschka P, et al.: MicroRNA (miR) expression signatures in molecular subsets of cytogenetically normal (CN) acute myeloid leukemia (AML): a Cancer and Leukemia Group B (CALGB) study. [Abstract] J Clin Oncol 25 (Suppl 18): A-7010, 359s, 2007.

Kolitz JE, George SL, Marcucci G, et al.: A randomized comparison of induction therapy for untreated acute myeloid leukemia (AML) in patients < 60 years using p-glycoprotein (Pgp) modulation with valspodar (PSC833): preliminary results of Cancer and Leukemia Group B study 19808. [Abstract] Blood 106 (11): A-407, 2005.

Langer C, Maharry K, Mrózek K, et al.: Low Meningioma 1 (MN1) gene expression to predict outcome in cytogenetically normal acute myeloid leukemia (CN-AML): A Cancer and Leukemia Group B (CALGB) study. [Abstract] J Clin Oncol 26 (Suppl 15): A-7011, 2008.

Langer C, Radmacher MD, Ruppert AS, Whitman SP, Paschka P, Mrozek K, Baldus CD, Vukosavljevic T, Liu CG, Ross ME, Powell BL, de la Chapelle A, Kolitz JE, Larson RA, Marcucci G, Bloomfield CD. High BAALC expression associates with other molecular prognostic markers, poor outcome and a distinct gene-expression signature in cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B (CALGB) study. Blood. 2008 Mar 31; [Epub ahead of print]

Marcucci G, Maharry K, Radmacher MD, Mrózek K, Vukosavljevic T, Paschka P, Whitman SP, Langer C, Baldus CD, Liu CG, Ruppert AS, Powell BL, Carroll AJ, Caligiuri MA, Kolitz JE, Larson RA, Bloomfield CD. Prognostic Significance of, and Gene and MicroRNA Expression Signatures Associated With, CEBPA Mutations in Cytogenetically Normal Acute Myeloid Leukemia With High-Risk Molecular Features: A Cancer and Leukemia Group B Study. J Clin Oncol. 2008 Sep 22; [Epub ahead of print]

Paschka P, Marcucci G, Ruppert AS, Whitman SP, Mrózek K, Maharry K, Langer C, Baldus CD, Zhao W, Powell BL, Baer MR, Carroll AJ, Caligiuri MA, Kolitz JE, Larson RA, Bloomfield CD. Wilms Tumor 1 Gene Mutations Independently Predict Poor Outcome in Adults With Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study. J Clin Oncol. 2008 Jun 16; [Epub ahead of print]

Langer C, Ruppert, AS, Radmacher MD, et al.: High BAALC expression associates with other molecular prognostic markers, poor outcome and a distinct gene expression signature in cytogenetically normal acute myeloid leukemia (CN AML): a Cancer and Leukemia Group B (CALGB) study. [Abstract] J Clin Oncol 25 (Suppl 18): A-7013, 360s, 2007.

Marcucci G, Maharry K, Radmacher MD, et al.: Gene and microRNA (miRNA) expression signatures and prognostic significance of CEBPA mutations in cytogenetically normal (CN) acute myeloid leukemia (AML) with high-risk molecular features: a Cancer and Leukemia Group B (CALGB) study . [Abstract] Blood 110 (11): A-104, 2007.

Marcucci G, Maharry K, Whitman SP, Vukosavljevic T, Paschka P, Langer C, Mrozek K, Baldus CD, Carroll AJ, Powell BL, Kolitz JE, Larson RA, Bloomfield CD. High Expression Levels of the ETS-Related Gene, ERG, Predict Adverse Outcome and Improve Molecular Risk-Based Classification of Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study. J Clin Oncol. 2007 Jun 18; [Epub ahead of print]

Whitman SP, Ruppert AS, Marcucci G, Mrozek K, Paschka P, Langer C, Baldus CD, Wen J, Vukosavljevic T, Powell BL, Carroll AJ, Kolitz JE, Larson RA, Caligiuri MA, Bloomfield CD. Long-term disease-free survivors with cytogenetically normal acute myeloid leukemia and MLL partial tandem duplication: a Cancer and Leukemia Group B study. Blood. 2007 Mar 6; [Epub ahead of print]

Paschka P, Marcucci G, Ruppert AS, Mrozek K, Chen H, Kittles RA, Vukosavljevic T, Perrotti D, Vardiman JW, Carroll AJ, Kolitz JE, Larson RA, Bloomfield CD; Cancer and Leukemia Group B. Adverse prognostic significance of KIT mutations in adult acute myeloid leukemia with inv(16) and t(8;21): a Cancer and Leukemia Group B Study. J Clin Oncol. 2006 Aug 20;24(24):3904-11.

Kolitz JE, George SL, Baer MR, Lee EJ, Bloomfield CD, Larson RA; Cancer and Leukemia Group B (CALGB) trials in younger and older adults. P-glycoprotein (Pgp) modulation in untreated acute myeloid leukemia (AML): Cancer and Leukemia Group B (CALGB) trials in younger and older adults. Ann Hematol. 2004;83 Suppl 1:S103-4. No abstract available.

Responsible Party:	Monica M Bertagnolli, Cancer and Leukemia Group B
ClinicalTrials.gov Identifier:	NCT00006363 History of Changes
Other Study ID Numbers:	CDR0000068234, U10CA031946, CALGB-19808
Study First Received:	October 4, 2000
Last Updated:	June 21, 2011
Health Authority:	United States: Food and Drug Administration

Keywords provided by Cancer and Leukemia Group B:

untreated adult acute myeloid leukemia
adult acute erythroid leukemia (M6)
adult acute myeloblastic leukemia without maturation (M1)
adult acute myeloblastic leukemia with maturation (M2)
adult acute myelomonocytic leukemia (M4)
adult acute monoblastic leukemia (M5a)
adult acute eosinophilic leukemia
adult acute basophilic leukemia

adult acute megakaryoblastic leukemia (M7)
adult acute monocytic leukemia (M5b)
adult acute minimally differentiated myeloid leukemia (M0)
adult acute myeloid leukemia with 11q23 (MLL) abnormalities
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)

Additional relevant MeSH terms:

Leukemia
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Neoplasms by Histologic Type
Neoplasms
Busulfan
Daunorubicin
Etoposide
Immunosuppressive Agents
Immunologic Factors

Physiological Effects of Drugs
Pharmacologic Actions
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Therapeutic Uses
Myeloablative Agonists
Antibiotics, Antineoplastic
Antineoplastic Agents, Phytogenic

ClinicalTrials.gov processed this record on February 12, 2012