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: March 26, 2014
Last verified: December 2013
  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 acute myeloid leukemia.


Condition Intervention Phase
Adult Acute Basophilic Leukemia
Adult Acute Eosinophilic Leukemia
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(15;17)(q22;q12)
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:
  • Achievement of 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.

  • Incidence and severity of toxicity of each induction/consolidation regimen as assessed by NCI CTCAE v4.0 [ Time Frame: At each course to 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's standard adverse event (AE) 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


Estimated Enrollment: 111
Study Start Date: October 2008
Estimated Primary Completion Date: July 2015 (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 once daily 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
  • Novantrone
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 oral sirolimus once daily on days 2-9, mitoxantrone hydrochloride IV over 15 minutes once daily, etoposide IV over 1 hour once daily, and cytarabine IV over 3 hours once daily on days 4-8 or 5-9.
Drug: mitoxantrone hydrochloride
Given IV
Other Names:
  • CL 232315
  • DHAD
  • DHAQ
  • Novantrone
Drug: cytarabine
Given IV
Other Names:
  • ARA-C
  • arabinofuranosylcytosine
  • arabinosylcytosine
  • Cytosar-U
  • cytosine arabinoside
Drug: sirolimus
Given orally
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 CR + CRc + 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 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 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 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: This is a multicenter, randomized study. Patients are stratified according to disease status (relapse ≤ 6 months after achieving first complete remission [CR] vs relapse between 6-12 months after achieving first CR vs refractory to ≤ 2 courses of initial conventional induction chemotherapy vs refractory to ≤ 1 course of first reinduction chemotherapy). Patients are randomized to 1 of 3 treatment arms. Induction therapy:

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

ARM II: Patients receive alvocidib IV over 4.5 hours once daily 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 oral sirolimus once daily on days 2-9, mitoxantrone hydrochloride IV over 15 minutes once daily, etoposide IV over 1 hour once daily, and cytarabine IV over 3 hours once daily on days 4-8 or 5-9.

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:

  • Morphologically confirmed acute myeloid leukemia (AML)

    • Bone marrow blasts ≥ 10% by bone marrow aspiration, smears, or touch preps of marrow biopsy
  • Relapsed or refractory disease meeting 1 of the following criteria:

    • Relapsed ≤ 6 months after first complete remission (CR)
    • Relapsed between 6-12 months after first CR
    • Refractory to initial conventional induction chemotherapy (≤ 2 courses) or to first reinduction chemotherapy (≤ 1 course)

      • Must have marrow documentation of residual leukemia post-induction chemotherapy (i.e., ≥ 10% blasts)
  • Patients who have relapsed more than 1 year after achieving first CR or are in second relapse or greater are not eligible
  • History of CNS leukemia allowed provided there is no current CNS involvement as documented by cerebrospinal fluid (CSF) examination (i.e., negative CSF by lumbar puncture)
  • Concurrent registration on protocol ECOG-E3903 required
  • No acute promyelocytic leukemia (confirmed by expression of the PML-RARα fusion protein) unless patient is ineligible for an ECOG APL trial OR if tretinoin or arsenic trioxide is not planned as part of the treatment regimen
  • ECOG performance status 0-2
  • Creatinine ≤ 2.0 mg/dL
  • Direct bilirubin < 2.0 mg/dL (does not apply if liver dysfunction is due to leukemia infiltration)
  • SGOT (AST) < 4 times upper limit of normal (does not apply if liver dysfunction is due to leukemia infiltration)
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • Shortening fraction ≥ 24% or normal by ECHO
  • Cardiac ejection fraction normal by pretreatment MUGA scan or ECHO (i.e., resting ejection fraction ≥ 50% or ≥ 5% increase with exercise)
  • No myocardial infarction within the past 3 months
  • No history of uncontrolled congestive heart failure or cardiac arrhythmia
  • No intercurrent organ damage or medical problems that would prohibit therapy or jeopardize the outcome of therapy
  • No active or unresolved infection uncontrolled by antibiotics
  • No current evidence of invasive fungal infection, including positive blood or deep tissue cultures or stains
  • No other active tumor likely to interfere with the patient's treatment for AML or to compromise the patient's morbidity or mortality substantially
  • No concurrent routine use of hematopoietic growth factors
  • Recovered from toxicities of prior chemotherapy and radiotherapy
  • No prior allogeneic or autologous stem cell transplantation
  • No prior carboplatin, topotecan hydrochloride, alvocidib, or sirolimus
  • At least 24 hours since prior hydroxyurea for rapidly rising blast count control (> 10,000/mm^3/day or above 50,000/mm^3)
  • Maximum cumulative dose of prior doxorubicin hydrochloride or daunorubicin must be < 300 mg/m^2
  • Maximum cumulative dose of prior idarubicin or mitoxantrone hydrochloride must be < 100 mg/m^2
  Contacts and Locations
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 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 Hazelton
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
Mount Nittany Medical Center
State College, Pennsylvania, United States, 16803
Geisinger Medical Group
State College, Pennsylvania, United States, 16801
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 Eastern Cooperative Oncology 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
Study First Received: March 11, 2008
Last Updated: March 26, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Congenital Abnormalities
Leukemia
Leukemia, Basophilic, Acute
Leukemia, Eosinophilic, Acute
Leukemia, Erythroblastic, Acute
Leukemia, Megakaryoblastic, Acute
Leukemia, Monocytic, Acute
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Leukemia, Myelomonocytic, Acute
Leukemia, Myelomonocytic, Chronic
Hypereosinophilic Syndrome
Neoplasms by Histologic Type
Neoplasms
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Myelodysplastic-Myeloproliferative Diseases
Eosinophilia
Leukocyte Disorders
Cytarabine
Sirolimus
Everolimus
Etoposide phosphate
Flavopiridol
Etoposide
Mitoxantrone
Carboplatin
Topotecan
Antimetabolites, Antineoplastic

ClinicalTrials.gov processed this record on April 17, 2014