Combination Chemotherapy Plus PSC 833 Followed by Interleukin-2 in Treating Patients With Acute Myelogenous Leukemia

Leukemia Clinical Trial

Official title:

Phase I Study of MDR Modulation With PSC-833 (NSC# 648265) With a Pilot Study of Cytogenetic Risk-Adapted Consolidation Followed by a Phase II Pilot Study of Immunotherapy With RIL-2 (NSC # 373364) in Previously Untreated Patients With AML< 60 Years

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00002925
• Other study ID #: CDR0000065333
• Secondary ID: U10CA031946CLB-9
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: November 1, 1999
• Last updated: November 29, 2012
• Start date: February 1997
• Est. completion date: June 2010

Study information

• Verified date: March 2011
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Some cancers may become resistant to chemotherapy drugs. Combining PSC 833 with chemotherapy may reduce resistance to the drugs and allow the cancer cells to be killed. Interleukin-2 may stimulate a person's white blood cells to kill leukemia cells.

PURPOSE: Phase I/II trial to study the effectiveness of combination chemotherapy plus PSC 833 followed by additional chemotherapy or peripheral stem cell transplantation and interleukin-2 in treating patients with untreated acute myelogenous leukemia.

Description:

OBJECTIVES: I. Determine the maximum tolerated dose (MTD) of daunorubicin when used in combination with etoposide, cytarabine, and PSC 833 (ADEP), and in combination with etoposide and cytarabine (ADE) in previously untreated patients with acute myelogenous leukemia who are less than 60 years. II. Determine the MTD of etoposide when used in combination with a constant dose of daunorubicin and cytarabine (ADE) in these patients. III. Determine the feasibility and toxic effects of administering postremission therapy in a risk adapted fashion, such that patients with favorable cytogenetic findings receive three intensifications with high dose cytarabine (HiDAC), while average to poor risk patients receive HiDAC/etoposide/filgrastim (G-CSF) for consolidation therapy and stem cell mobilization followed by peripheral stem cell (PBSC) transplant using busulfan/etoposide as the preparative regimen. IV. Determine the feasibility and toxic effects of the consolidation sequence of HiDAC/etoposide/G-CSF followed by 2 courses of HiDAC in patients who would otherwise receive PBSC transplant, but are unable to do so for logistical or institutional reasons. V. Determine the feasibility of intermittent administration of high dose subcutaneous interleukin-2 (IL-2) in combination with continuous low dose subcutaneous IL-2 in patients recovering from PBSC transplant or intensive consolidation chemotherapy.

OUTLINE: This is a dose escalation study of daunorubicin in the induction therapy portion, with a separate dose escalation study of etoposide in the same portion. Patients are treated with three phases of treatment: induction, intensification, and postremission therapy. Induction therapy: Patients receive cytarabine IV as a continuous infusion on days 1-7 plus daunorubicin IV over 30 minutes and etoposide IV over 2 hours on days 1-3 (ADE regimen). Some patients also receive PSC 833 IV as a continuous infusion on days 1-3 (ADEP regimen). This course may be repeated 14 days later. Cohorts of 9 patients each receive escalating doses of daunorubicin until the maximum tolerated dose (MTD) is reached. The MTD is defined as the dose at which 3 of 9 patients experience dose limiting toxicity. Escalations are conducted separately for the ADE and ADEP regimens. Other cohorts of 9 patients each receive escalating doses of etoposide with constant doses of daunorubicin in the ADE regimen. The MTD is described in the same manner. Intensification therapy: Arm I (patients with certain genetic characteristics in their leukemia cells): Patients receive 3 additional courses of cytarabine IV over 3 hours, twice a day, for 3 days. Courses are repeated every 28 days. Arm II (patients who do not have these genetic characteristics): Patients undergo a peripheral blood stem cell (PBSC) transplant. Patients first receive high dose cytarabine IV over 2 hours on days 1-4, etoposide IV as a continuous infusion on days 1-4, and filgrastim (G-CSF) subcutaneously beginning on day 5 until blood counts recover. PBSC are then collected. Approximately 4-6 weeks later, patients receive oral busulfan 4 times a day on days 1-4 and etoposide IV over 4 hours on day 5. PBSC are reinfused on day 7. G-CSF is administered subcutaneously beginning on day 7 until blood cell counts recover. Arm III (patients who cannot undergo a PBSC transplant): Patients receive cytarabine, etoposide, and G-CSF as in arm II, then high dose cytarabine as in arm I. Postremission therapy (all patients): Patients receive low dose interleukin-2 (IL-2) by daily injection for 2 weeks. On day 15, patients begin receiving intermittent high dose IL-2 three days a week. Patients alternate these courses of IL-2: 14 days of low dose IL-2, 3 days of high dose IL-2, 1 day of rest, low dose IL-2 for 10 days, then 3 days of high dose IL-2, then 1 day of rest. This course is repeated 3 times. Patients then receive another 16 day course of low dose IL-2. Patients are followed at 1 month, then every 3 months for 2 years, then every 6 months for 2 years, then annually thereafter.

PROJECTED ACCRUAL: Approximately 410 patients will be accrued into this study within 36 months.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 410
• Est. completion date: June 2010
• Est. primary completion date: November 2003
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 15 Years to 59 Years

Eligibility

DISEASE CHARACTERISTICS: Histologically proven acute myelogenous leukemia, except M3

PATIENT CHARACTERISTICS: Age: 15 to 59 Performance status: Not specified Life expectancy:

Not specified Hematopoietic: No prior hematologic malignancy, myeloproliferative disorder, myelodysplastic syndrome, or paroxysmalnocturnal hemoglobinuria No unexplained cytopenias greater than 3 months in duration Hepatic: Not specified Renal: Not specified

PRIOR CONCURRENT THERAPY: Biologic therapy: No prior biologic therapy No prior treatment for leukemia except leukapheresis Chemotherapy: No prior chemotherapy except hydroxyurea which may be used for emergency therapy of hyperleukocytosis Endocrine therapy: Not specified Radiotherapy: Prior cranial radiation therapy allowed for CNS leukostasis Surgery: Not specified

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Leukemia

Intervention

Drug:
• ara-C

• Daunorubicin

• Etoposide

• PSC-833

Biological:
• Aldesleukin

Locations

Country	Name	City	State
United States	Marlene & Stewart Greenebaum Cancer Center, University of Maryland	Baltimore	Maryland
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Vermont Cancer Center	Burlington	Vermont
United States	Lineberger Comprehensive Cancer Center, UNC	Chapel Hill	North Carolina
United States	Medical University of South Carolina	Charleston	South Carolina
United States	University of Chicago Cancer Research Center	Chicago	Illinois
United States	University of Illinois at Chicago Health Sciences Center	Chicago	Illinois
United States	Ellis Fischel Cancer Center - Columbia	Columbia	Missouri
United States	Duke Comprehensive Cancer Center	Durham	North Carolina
United States	University of Iowa Hospitals and Clinics	Iowa City	Iowa
United States	University of California San Diego Cancer Center	La Jolla	California
United States	CCOP - Southern Nevada Cancer Research Foundation	Las Vegas	Nevada
United States	Norris Cotton Cancer Center	Lebanon	New Hampshire
United States	CCOP - North Shore University Hospital	Manhasset	New York
United States	North Shore University Hospital	Manhasset	New York
United States	University of Tennessee, Memphis Cancer Center	Memphis	Tennessee
United States	CCOP - Mount Sinai Medical Center	Miami Beach	Florida
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	Mount Sinai Medical Center, NY	New York	New York
United States	New York Presbyterian Hospital - Cornell Campus	New York	New York
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Rhode Island Hospital	Providence	Rhode Island
United States	MBCCOP - Massey Cancer Center	Richmond	Virginia
United States	Barnes-Jewish Hospital	Saint Louis	Missouri
United States	UCSF Cancer Center and Cancer Research Institute	San Francisco	California
United States	CCOP - Syracuse Hematology-Oncology Associates of Central New York, P.C.	Syracuse	New York
United States	State University of New York - Upstate Medical University	Syracuse	New York
United States	Walter Reed Army Medical Center	Washington	District of Columbia
United States	CCOP - Christiana Care Health Services	Wilmington	Delaware
United States	CCOP - Southeast Cancer Control Consortium	Winston-Salem	North Carolina
United States	Comprehensive Cancer Center of Wake Forest University Baptist Medical Center	Winston-Salem	North Carolina
United States	University of Massachusetts Memorial Medical Center	Worcester	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

References & Publications (23)

Baldus CD, Tanner SM, Ruppert AS, Whitman SP, Archer KJ, Marcucci G, Caligiuri MA, Carroll AJ, Vardiman JW, Powell BL, Allen SL, Moore JO, Larson RA, Kolitz JE, de la Chapelle A, Bloomfield CD. BAALC expression predicts clinical outcome of de novo acute m — View Citation

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Kolitz JE, George SL, Barrier R, et al.: A novel post-remission consolidation regimen for patients with acute myeloid leukemia (AML) < 60 years old with normal or unfavorable cytogenetics: results from CALGB 9621. [Abstract] Blood 102 (11 Pt 1): A-609, 20

Kolitz JE, George SL, Barrier R, et al.: Treatment of core binding factor (CBF) acute myeloid leukemia (AML) with post-remission high-dose cytarabine (HiDAC): results from CALGB 9621. [Abstract] Blood 102 (11 Pt 1): A-612, 2003.

Kolitz JE, George SL, Dodge RK, Hurd DD, Powell BL, Allen SL, Velez-Garcia E, Moore JO, Shea TC, Hoke E, Caligiuri MA, Vardiman JW, Bloomfield CD, Larson RA; Cancer and Leukemia Group B. Dose escalation studies of cytarabine, daunorubicin, and etoposide w — View Citation

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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, Mrózek K, Baldus CD, Vukosavljevic T, Liu CG, Ross ME, Powell BL, de la Chapelle A, Kolitz JE, Larson RA, Marcucci G, Bloomfield CD; Cancer and Leukemia Group B (CALGB). High BAALC expression associates with other molecular prognostic markers, poor outcome, and a distinct gene-expression signature in cytogenetically normal patients younger than 60 years with acute myeloid leukemia: a Cancer and Leukemia Group B (CALGB) study. Blood. 2008 Jun 1;111(11):5371-9. doi: 10.1182/blood-2007-11-124958. Epub 2008 Mar 31. — View Citation

Marcucci G, Baldus CD, Ruppert AS, et al.: Overexpression of the ERG gene is an adverse prognostic factor in acute myeloid leukemia (AML) with normal cytogenetics (NC): a Cancer and Leukemia Group B study (CALGB). [Abstract] Blood 106 (11): A-335, 2005.

Marcucci G, Baldus CD, Ruppert AS, Radmacher MD, Mrózek K, Whitman SP, Kolitz JE, Edwards CG, Vardiman JW, Powell BL, Baer MR, Moore JO, Perrotti D, Caligiuri MA, Carroll AJ, Larson RA, de la Chapelle A, Bloomfield CD. Overexpression of the ETS-related ge — View Citation

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 Nov 1;26(31):5078-87. doi: 10.1200/JCO.2008.17.5554. Epub 2008 Sep 22. Erratum in: J Clin Oncol. 2008 Dec 20;26(36):6021. — View Citation

Marcucci G, Maharry K, Whitman SP, Vukosavljevic T, Paschka P, Langer C, Mrózek K, Baldus CD, Carroll AJ, Powell BL, Kolitz JE, Larson RA, Bloomfield CD; Cancer and Leukemia Group B Study. 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 Aug 1;25(22):3337-43. Epub 2007 Jun 18. — View Citation

Marcucci G, Radmacher MD, Ruppert AS, et al.: Independent validation of prognostic relevance of a previously reported gene-expression signature in acute myeloid leukemia (AML) with normal cytogenetics (NC): a Cancer and Leukemia Group B (CALGB) study. [Ab

Metzeler KH, Hummel M, Bloomfield CD, et al.: An 86-probe gene expression signature can predict survival in AML with normal karyotype independently of FLT3 ITD and NPM1 mutation status: a collaborative study from the AMLCG and CALGB study groups. [Abstract] Blood 110 (11): A-596, 2007.

Mrózek K, Prior TW, Edwards C, Marcucci G, Carroll AJ, Snyder PJ, Koduru PR, Theil KS, Pettenati MJ, Archer KJ, Caligiuri MA, Vardiman JW, Kolitz JE, Larson RA, Bloomfield CD. Comparison of cytogenetic and molecular genetic detection of t(8;21) and inv(16 — View Citation

Paschka P, Marcucci G, Ruppert AS, Mrózek 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. — View Citation

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 Oct 1;26(28):4595-602. doi: 10.1200/JCO.2007.15.2058. Epub 2008 Jun 16. — View Citation

Radmacher MD, Marcucci G, Ruppert AS, Mrózek K, Whitman SP, Vardiman JW, Paschka P, Vukosavljevic T, Baldus CD, Kolitz JE, Caligiuri MA, Larson RA, Bloomfield CD; Cancer and Leukemia Group B. Independent confirmation of a prognostic gene-expression signat — View Citation

Sekeres MA, Dodge RK, Bloomfield CD, et al.: Racial differences in prognostic factors and outcome in acute myeloid leukemia (AML): a Cancer and Leukemia Group B (CALGB) study. [Abstract] Blood 100 (11 Pt 1): A-323, 2002.

Sekeres MA, Peterson B, Dodge RK, Mayer RJ, Moore JO, Lee EJ, Kolitz J, Baer MR, Schiffer CA, Carroll AJ, Vardiman JW, Davey FR, Bloomfield CD, Larson RA, Stone RM; Cancer and Leukemia Group B. Differences in prognostic factors and outcomes in African Americans and whites with acute myeloid leukemia. Blood. 2004 Jun 1;103(11):4036-42. Epub 2004 Feb 19. — View Citation

Whitman SP, Archer KJ, Feng L, Baldus C, Becknell B, Carlson BD, Carroll AJ, Mrózek K, Vardiman JW, George SL, Kolitz JE, Larson RA, Bloomfield CD, Caligiuri MA. Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukem — View Citation

Whitman SP, Ruppert AS, Marcucci G, Mrózek 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 Jun 15;109(12):5164-7. Epub 2007 Mar 6. — View Citation

* Note: There are 23 references in all — Click here to view all references