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Comparing Three Different Combination Chemotherapy Regimens in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00634244
First received: March 11, 2008
Last updated: October 10, 2014
Last verified: May 2014
  Purpose

This randomized phase II trial is comparing three different combination chemotherapy regimens to see how well they work in treating patients with relapsed or refractory acute myeloid leukemia. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells. It is not yet known which combination chemotherapy regimen is more effective in treating patients with relapsed or refractory acute myeloid leukemia.


Condition Intervention Phase
Adult Acute Megakaryoblastic Leukemia (M7)
Adult Acute Minimally Differentiated Myeloid Leukemia (M0)
Adult Acute Monoblastic Leukemia (M5a)
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 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)
Recurrent Adult Acute Myeloid Leukemia
Drug: alvocidib
Drug: mitoxantrone hydrochloride
Drug: carboplatin
Drug: cytarabine
Drug: sirolimus
Drug: etoposide
Drug: topotecan hydrochloride
Other: laboratory biomarker analysis
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Randomized Trial of Carboplatin and Topotecan; Flavopiridol, Mitoxantrone and Cytosine Arabinoside; and Sirolimus, Mitoxantrone, Etoposide and Cytosine Arabinoside for the Treatment of Adults With Primary Refractory or Initial Relapse of Acute Myelogenous Leukemia (AML)

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Observed response rate (CR+CRc+CRi) [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    The confidence interval for the observed response rate will be calculated by the Atkinson and Brown procedure.

  • Treatment-related toxicity data, as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 3 years ] [ Designated as safety issue: Yes ]
    Treatment-related toxicities will be monitored closely for each treatment arm. Toxicity will be monitored using ECOG-ACRIN's standard adverse event mechanism.


Secondary Outcome Measures:
  • Rate of treatment failure [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]

    The definition of treatment failure will include:

    • >= 5% leukemic blasts at the time of pre-consolidation marrow
    • Death during/following induction chemotherapy (pre-consolidation)
    • Persisting marrow hypoplasia and pancytopenia for >= 2 months after chemotherapy
    • CNS or extramedullary disease at the time of pre-consolidation
    • Leukemia persistence after completion of induction treatment; leukemia persistence is defined as greater than 10% residual blasts on marrow biopsy done 5-7 days after completion of induction chemotherapy


Other Outcome Measures:
  • Bcl-2 expression [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    Compared between responders and non-responders using the Wilcoxon rank sum test.

  • Change in topoisomerase I expression [ Time Frame: Baseline to 3 days after initiation of therapy ] [ Designated as safety issue: No ]
    Compared between responders and non-responders using the Wilcoxon rank sum test.


Enrollment: 92
Study Start Date: October 2008
Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (carboplatin and topotecan hydrochloride)
Patients receive carboplatin and topotecan hydrochloride IV continuously over 24 hours on days 1-5.
Drug: carboplatin
Given IV
Other Names:
  • Carboplat
  • CBDCA
  • JM-8
  • Paraplat
  • Paraplatin
Drug: topotecan hydrochloride
Given IV
Other Names:
  • hycamptamine
  • Hycamtin
  • SKF S-104864-A
  • TOPO
Other: laboratory biomarker analysis
Correlative studies
Experimental: Arm II (alvocidib, mitoxantrone hydrochloride, cytarabine)
Patients receive alvocidib IV over 4.5 hours QD on days 1-3, cytarabine IV continuously over 72 hours on days 6-8, and mitoxantrone hydrochloride IV over 1-2 hours on day 9.
Drug: alvocidib
Given IV
Other Names:
  • FLAVO
  • flavopiridol
  • HMR 1275
  • L-868275
Drug: mitoxantrone hydrochloride
Given IV
Other Names:
  • CL 232315
  • DHAD
  • DHAQ
Drug: cytarabine
Given IV
Other Names:
  • ARA-C
  • arabinofuranosylcytosine
  • arabinosylcytosine
  • Cytosar-U
  • cytosine arabinoside
Other: laboratory biomarker analysis
Correlative studies
Experimental: Arm III (mitoxantrone hydrochloride, cytarabine, sirolimus)
Patients receive sirolimus PO QD on days 2-9, mitoxantrone hydrochloride IV over 15 minutes QD, etoposide IV over 1 hour QD, and cytarabine IV over 3 hours QD on days 4-8 or 5-9. (Closed to accrual)
Drug: mitoxantrone hydrochloride
Given IV
Other Names:
  • CL 232315
  • DHAD
  • DHAQ
Drug: cytarabine
Given IV
Other Names:
  • ARA-C
  • arabinofuranosylcytosine
  • arabinosylcytosine
  • Cytosar-U
  • cytosine arabinoside
Drug: sirolimus
Given PO
Other Names:
  • AY 22989
  • Rapamune
  • rapamycin
  • SLM
Drug: etoposide
Given IV
Other Names:
  • EPEG
  • VP-16
  • VP-16-213
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the complete remission (CR) + cytogenic complete remission (CRc) + morphologic complete remission with incomplete blood count recovery (CRi) rate of carboplatin and topotecan; flavopiridol, mitoxantrone and cytosine arabinoside and sirolimus, mitoxantrone, etoposide and cytosine arabinoside in adult patients with refractory or relapsed acute myeloid leukemia (AML).

II. To determine the rate of treatment failure of these regimens. III. To determine the incidence and severity of toxicities of these regimens. IV. To analyze the predictive value of blast cell properties that have been suggested to determine response. (Correlative laboratory studies) V. To determine whether pretreatment levels of B-cell chronic lymphocytic leukemia (CLL)/lymphoma 2 (Bcl-2) or, alternatively, whether a therapy-induced change in topoisomerase I levels correlates with response to this regimen. (Correlative laboratory studies) VI. To assess the impact of clonal evolution by comparing cytogenetic abnormalities at the time of relapse with those at initial diagnosis and correlating these abnormalities and changes with response to the treatment regimens in this protocol. (Cytogenetic and fluorescent in situ hybridization [FISH] studies) VII. Panel FISH studies for common AML rearrangements will be performed on relapse AML specimens to determine the presence of these recurrent AML abnormalities and to evaluate for subtle additional abnormalities consistent with clonal evolution in these relapse specimens. (Cytogenetic and FISH studies)

OUTLINE: Patients are randomized to 1 of 3 treatment arms.

INDUCTION THERAPY:

ARM I: Patients receive carboplatin and topotecan hydrochloride intravenously (IV) continuously over 24 hours on days 1-5.

ARM II: Patients receive alvocidib IV over 4.5 hours once daily (QD) on days 1-3, cytarabine IV continuously over 72 hours on days 6-8, and mitoxantrone hydrochloride IV over 1-2 hours on day 9.

ARM III: Patients receive sirolimus orally (PO) QD on days 2-9, mitoxantrone hydrochloride IV over 15 minutes QD, etoposide IV over 1 hour QD, and cytarabine IV over 3 hours QD on days 4-8 or 5-9. (Closed to accrual)

After completion of induction therapy, patients in all arms undergo bone marrow aspirate and biopsy. Patients with persistent leukemia (i.e., leukemic blasts >= 10%) are removed from study and are offered alternative therapy at the discretion of the investigator. Patients who achieve CR proceed to consolidation therapy or receive alternative therapy at the discretion of the investigator.

CONSOLIDATION THERAPY: Beginning within 2-6 weeks after documentation of CR, patients may receive up to 2 additional courses of the same treatment they received during induction therapy. Courses repeat every 4-10 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed periodically for up to 3 years.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have morphologic proof (from bone marrow aspirate, smears or touch preps of marrow biopsy) of acute myelogenous leukemia (AML) with >= 10% blasts within two weeks prior to induction randomization

    • NOTE: Patients must be registered to E3903 (Ancillary Laboratory Protocol for Collecting Diagnostic Material on Patients Considered for Eastern Cooperative Oncology Group [ECOG]-American College of Radiology Imaging Network [ACRIN] Treatment Trials for Leukemia or Related Hematologic Disorders) and must undergo eligibility testing for the study by multiparameter flow cytometry
    • All immunodiagnoses are eligible for E1906, except acute promyelocytic leukemia (APL) (proven by the presence of promyelocytic leukemia [PML]/retinoic acid receptor [RAR] alpha); cases of APL can become eligible if the patient is ineligible for an ECOG-ACRIN APL trial or if all-trans retinoic acid or arsenic trioxide is not planned as part of the treatment regimen
  • Patients must qualify for one of the following:

    • Relapse =< 6 months after first CR, dated from documentation of CR to documentation of relapse
    • Relapse between 6-12 months after first CR
  • Refractory to conventional initial induction chemotherapy (=< 2 courses) or to first reinduction (=< 1 course)
  • Patients who have relapsed > 1 year after achieving first CR or are in >= second relapse are not eligible
  • Patients who have had a prior allogeneic OR autologous stem cell transplant are not eligible
  • No history of recent myocardial infarction (within three months), uncontrolled congestive heart failure, or uncontrolled cardiac arrhythmia
  • Normal cardiac ejection fraction by pretreatment multi gated acquisition scan (MUGA) or echocardiogram within 4 weeks prior to randomization (resting ejection fraction >= 50% or >= 5% increase with exercise), shortening fraction by echocardiogram >= 24%, or to within the normal range of values for the institution
  • Prior treatment to doses of any of the following:

    • < 300 mg/m^2 of doxorubicin
    • < 300 mg/m^2 of daunorubicin
    • < 100 mg/m^2 of idarubicin
    • < 100 mg/m^2 of mitoxantrone
  • No prior treatment with carboplatin, topotecan, flavopiridol, or sirolimus
  • Serum creatinine =< 2.0 mg/dL
  • Serum direct bilirubin < 2.0 mg/dL
  • Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) < 4 x upper limit of normal

    • The above stipulation for normal hepatic function does not apply if liver dysfunction is due to leukemia infiltration
  • Prior to study entry, patients must have recovered from toxicities of prior chemotherapy and radiotherapy; for patients refractory to induction chemotherapy (patient subgroup outlined above), marrow documentation of residual leukemia post chemotherapy and qualification for remaining eligibility criteria are needed prior to study entry (this does not require >= 30% marrow blasts to be evident but a minimum of 10% blasts must be present in the marrow)

    • NOTE: Hydroxyurea is permitted within 4 weeks of study entry
  • ECOG performance status 0, 1 or 2
  • Not pregnant or breast feeding
  • Women of childbearing potential and sexually active males should use an accepted and effective method of contraception
  • No intercurrent organ damage or medical problems that would prohibit therapy; no active or unresolved infection
  • No current evidence of invasive fungal infection; such evidence includes positive blood or deep tissue cultures or stains
  • Patients with a history of central nervous system (CNS) leukemia are eligible if there is documentation of no current CNS involvement on cerebrospinal fluid (CSF) examination, (i.e., negative CSF by lumbar puncture)
  • Patients must not have another (i.e., prior) tumor which is currently active and likely to interfere with the patient's treatment for AML or which is likely to compromise the patient's morbidity or mortality substantially
  • Eligibility criteria for consolidation therapy:

    • Patients must have an ECOG performance status 0, 1 or 2
    • Patients must have documented CR
    • Patients must have an absence of infection or have infection controlled by antibiotics; patients who are septic will be excluded
    • Patients must have a serum creatinine clearance > 50 cc/minute
    • Patients must have a serum direct bilirubin < 2.0 mg/dl and alkaline phosphatase and SGOT (AST) < 4 x upper limits of normal
    • Patients must not have intercurrent organ damage or medical problems that will jeopardize the outcome of therapy
    • Patients must have a normal cardiac ejection fraction by MUGA or echocardiogram prior to consolidation (resting ejection fraction >= 50% or >= 5% increase with exercise), shortening fraction by echocardiogram >= 24%, or to within normal range of values for the institution prior to the first and second cycle of consolidation for arms B and C
    • NOTE: Arm C is closed to accrual
  • For arms B and C, patients must not have exceeded the following anthracycline doses or their equivalents:

    • < 300 mg/m^2 of doxorubicin
    • < 300 mg/m^2 of daunoribicin
    • < 100 mg/m^2 of idarubicin
    • < 100 mg/m^2 of mitoxantrone
    • NOTE: Arm C is closed to accrual
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00634244

Locations
United States, Alabama
University of Alabama at Birmingham
Birmingham, Alabama, United States, 35294
United States, Arizona
Mayo Clinic in Arizona
Scottsdale, Arizona, United States, 85259
United States, Florida
Mayo Clinic in Florida
Jacksonville, Florida, United States, 32224-9980
United States, Illinois
Northwestern University
Chicago, Illinois, United States, 60611
United States, Iowa
Siouxland Hematology Oncology Associates
Sioux City, Iowa, United States, 51101
United States, Maryland
Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center
Baltimore, Maryland, United States, 21287
United States, Massachusetts
Tufts Medical Center
Boston, Massachusetts, United States, 02111
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
United States, Ohio
The Jewish Hospital
Cincinnati, Ohio, United States, 45236
United States, Pennsylvania
Geisinger Medical Center
Danville, Pennsylvania, United States, 17822-2001
Geisinger Medical Center-Cancer Center Hazleton
Hazleton, Pennsylvania, United States, 18201
Penn State Milton S Hershey Medical Center
Hershey, Pennsylvania, United States, 17033-0850
Lewistown Hospital
Lewistown, Pennsylvania, United States, 17044
Geisinger Medical Group
State College, Pennsylvania, United States, 16801
Mount Nittany Medical Center
State College, Pennsylvania, United States, 16803
Geisinger Wyoming Valley
Wilkes-Barre, Pennsylvania, United States, 18711
United States, Tennessee
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, United States, 37232
United States, Wisconsin
University of Wisconsin Hospital and Clinics
Madison, Wisconsin, United States, 53792
Froedtert and the Medical College of Wisconsin
Milwaukee, Wisconsin, United States, 53226
Israel
Rambam Medical Center
Haifa, Israel, 31096
Sponsors and Collaborators
Investigators
Principal Investigator: Mark Litzow ECOG-ACRIN Cancer Research Group
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00634244     History of Changes
Other Study ID Numbers: NCI-2009-00520, NCI-2009-00520, CDR0000588834, E1906, E1906, U10CA021115, U10CA180820
Study First Received: March 11, 2008
Last Updated: October 10, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Leukemia
Leukemia, Erythroblastic, Acute
Leukemia, Megakaryoblastic, Acute
Leukemia, Monocytic, Acute
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Leukemia, Myelomonocytic, Acute
Leukemia, Myelomonocytic, Chronic
Bone Marrow Diseases
Hematologic Diseases
Myelodysplastic-Myeloproliferative Diseases
Myeloproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Alvocidib
Carboplatin
Cytarabine
Etoposide
Etoposide phosphate
Everolimus
Mitoxantrone
Sirolimus
Topotecan
Analgesics
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Antimetabolites
Antimetabolites, Antineoplastic

ClinicalTrials.gov processed this record on November 25, 2014