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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)


Phase 2
18 Years
65 Years
Open (Enrolling)
Both
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

Thank you

Trial Information

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)


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.


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

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Achievement of CR+CRc+CRi

Outcome Description:

The confidence interval for the observed response rate will be calculated by the Atkinson and Brown procedure.

Outcome Time Frame:

Up to 3 years

Safety Issue:

No

Principal Investigator

Mark Litzow

Investigator Role:

Principal Investigator

Investigator Affiliation:

Eastern Cooperative Oncology Group

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2009-00520

NCT ID:

NCT00634244

Start Date:

October 2008

Completion Date:

Related Keywords:

  • 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
  • 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

Name

Location

Johns Hopkins UniversityBaltimore, Maryland  21205
Mayo ClinicRochester, Minnesota  55905
Geisinger Medical CenterDanville, Pennsylvania  17822-0001
University of Wisconsin Hospital and ClinicsMadison, Wisconsin  53792-0001
Mayo Clinic in ArizonaScottsdale, Arizona  85259-5404
Mayo Clinic in FloridaJacksonville, Florida  32224
University of Alabama at BirminghamBirmingham, Alabama  35294-3300
Vanderbilt UniversityNashville, Tennessee  37232-6305
Northwestern UniversityChicago, Illinois  60611
Tufts Medical CenterBoston, Massachusetts  02111
Penn State Milton S Hershey Medical CenterHershey, Pennsylvania  17033
Froedtert and the Medical College of WisconsinMilwaukee, Wisconsin  53226
The Jewish HospitalCincinnati, Ohio  45236
Siouxland Hematology Oncology AssociatesSioux City, Iowa  51101