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

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Brief Title

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

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)

Brief Summary

      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.
    

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).

      NOTE: Since the CRc patients are required to be either CR or CRi, we only report the rate of
      CR+CRi in the results section.

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

      ARM B: 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 C: 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.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

The Rate of Complete Remission (CR+CRi)

Secondary Outcome

 The Rate of Treatment Failure

Condition

Adult Acute Megakaryoblastic Leukemia (M7)

Intervention

alvocidib

Study Arms / Comparison Groups

 Arm A (carboplatin and topotecan hydrochloride)
Description:  Patients receive carboplatin and topotecan hydrochloride IV continuously over 24 hours on days 1-5.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

92

Start Date

October 2008

Completion Date

October 2014

Primary Completion Date

September 2014

Eligibility Criteria

        Inclusion Criteria

        Induction Therapy:

          -  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)

          -  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

          -  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

          -  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)

        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 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

        Exclusion Criteria

        Induction therapy:

          -  Patients who have relapsed > 1 year after achieving first CR or are in >= second
             relapse

          -  Patients who have had a prior allogeneic OR autologous stem cell transplant

          -  History of recent myocardial infarction (within three months), uncontrolled congestive
             heart failure, or uncontrolled cardiac arrhythmia

          -  Prior treatment with carboplatin, topotecan, flavopiridol, or sirolimus

          -  Pregnant or breast feeding. Women of childbearing potential and sexually active males
             should use an accepted and effective method of contraception

          -  Intercurrent organ damage or medical problems that would prohibit therapy; no active
             or unresolved infection

          -  Current evidence of invasive fungal infection; such evidence includes positive blood
             or deep tissue cultures or stains

          -  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

        Consolidation therapy:

          -  Intercurrent organ damage or medical problems that will jeopardize the outcome of
             therapy

          -  For arms B and C, patients have exceeded the following anthracycline doses or their
             equivalents:

          -  < 300 mg/m^2 of doxorubicin

          -  < 300 mg/m^2 of daunorubicin

          -  < 100 mg/m^2 of idarubicin

          -  < 100 mg/m^2 of mitoxantrone
      

Gender

All

Ages

18 Years - 65 Years

Accepts Healthy Volunteers

No

Contacts

Mark Litzow, , 

Location Countries

Israel

Location Countries

Israel

Administrative Informations


NCT ID

NCT00634244

Organization ID

NCI-2009-00520

Secondary IDs

NCI-2009-00520

Responsible Party

Sponsor

Study Sponsor

National Cancer Institute (NCI)


Study Sponsor

Mark Litzow, Principal Investigator, ECOG-ACRIN Cancer Research Group


Verification Date

April 2015