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Adult Acute Megakaryoblastic Leukemia (M7)Phase 2NCT00634244

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

A Phase 2 study testing alvocidib, mitoxantrone hydrochloride and carboplatin in people with Adult Acute Megakaryoblastic Leukemia (M7) and Adult Acute Minimally Differentiated Myeloid Leukemia (M0), run by National Cancer Institute (NCI) at 20 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 to 65 years
What is being tested?
alvocidib, mitoxantrone hydrochloride and carboplatin
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
92 participants
Where
20 sitesin 2 countries
Study dates
Oct 2008to Oct 2014
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 65 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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

Who cannot join

  • 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
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  • 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

Trial locations and contacts

20 sites in 2 countries.

20 sites in 2 countries

United States19 sites

  • Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center

    Baltimore, Maryland, 21287

  • University of Alabama at Birmingham

    Birmingham, Alabama, 35294

  • Tufts Medical Center

    Boston, Massachusetts, 02111

  • Northwestern University

    Chicago, Illinois, 60611

  • The Jewish Hospital

    Cincinnati, Ohio, 45236

  • Geisinger Medical Center

    Danville, Pennsylvania, 17822-2001

  • Geisinger Medical Center-Cancer Center Hazleton

    Hazleton, Pennsylvania, 18201

  • Penn State Milton S Hershey Medical Center

    Hershey, Pennsylvania, 17033-0850

  • Mayo Clinic in Florida

    Jacksonville, Florida, 32224-9980

  • Lewistown Hospital

    Lewistown, Pennsylvania, 17044

  • University of Wisconsin Hospital and Clinics

    Madison, Wisconsin, 53792

  • Froedtert and the Medical College of Wisconsin

    Milwaukee, Wisconsin, 53226

  • Vanderbilt-Ingram Cancer Center

    Nashville, Tennessee, 37232

  • Mayo Clinic

    Rochester, Minnesota, 55905

  • Mayo Clinic in Arizona

    Scottsdale, Arizona, 85259

  • Siouxland Hematology Oncology Associates

    Sioux City, Iowa, 51101

  • Geisinger Medical Group

    State College, Pennsylvania, 16801

  • Mount Nittany Medical Center

    State College, Pennsylvania, 16803

  • Geisinger Wyoming Valley

    Wilkes-Barre, Pennsylvania, 18711

Other trials in United States

Israel1 site

  • Rambam Medical Center

    Haifa, 31096

Other trials in Israel

About this study

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)

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.

Read the detailed description

PRIMARY OBJECTIVES:

  1. 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.

Being tested
alvocidib, mitoxantrone hydrochloride, carboplatin, cytarabine, sirolimus
Keywords
Acute Myelogenous Leukemia (AML), Carboplatin, Topotecan, Flavopiridol, Mitoxantrone, Cytosine Arabinoside, Sirolimus, Etoposide
Medical subject headings
Leukemia, Megakaryoblastic, Acute, Leukemia, Monocytic, Acute, Leukemia, Myeloid, Acute, Congenital Abnormalities, Leukemia, Myelomonocytic, Acute, Leukemia, Erythroblastic, Acute

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • alvocidibDrug

    Also called FLAVO, flavopiridol, HMR 1275, L-868275

    Given IV

  • mitoxantrone hydrochlorideDrug

    Also called CL 232315, DHAD, DHAQ

    Given IV

  • carboplatinDrug

    Also called Carboplat, CBDCA, JM-8, Paraplat

    Given IV

  • cytarabineDrug

    Also called ARA-C, arabinofuranosylcytosine, arabinosylcytosine, Cytosar-U

    Given IV

  • sirolimusDrug

    Also called AY 22989, Rapamune, rapamycin, SLM

    Given PO

  • etoposideDrug

    Also called EPEG, VP-16, VP-16-213

    Given IV

  • topotecan hydrochlorideDrug

    Also called hycamptamine, Hycamtin, SKF S-104864-A, TOPO

    Given IV

Study groups in NCT00634244
Study groupRoleWhat they receive
Arm A (carboplatin and topotecan hydrochloride)ExperimentalPatients receive carboplatin and topotecan hydrochloride IV continuously over 24 hours on days 1-5.
Receives: Drug: carboplatin; Drug: topotecan hydrochloride
Arm B (alvocidib, mitoxantrone, cytarabine)ExperimentalPatients 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.
Receives: Drug: alvocidib; Drug: mitoxantrone hydrochloride; Drug: cytarabine
Arm C (sirolimus, mitoxantrone, etoposide, cytarabine)ExperimentalPatients 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)
Receives: Drug: mitoxantrone hydrochloride; Drug: cytarabine; Drug: sirolimus; Drug: etoposide

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. The Rate of Complete Remission (CR+CRi)

    CR requires: 1. peripheral blood counts: neutrophil count ≥ 1.0 x 10^9/L, platelet count ≥ 100 x 10^9/L, reduced hemoglobin concentration or hematocrit has no bearing on remission status, and leukemic blasts must not be present in the peripheral blood. 2. bone marrow aspirate and biopsy: maturation of all cell lines must be present, ≤ 5% blasts, auer rods must not be detectable. 3. extramedullary leukemia, such as central nervous system (CNS) or soft tissue involvement, must not be present. CRi requires that all criteria for complete remission be satisfied except patients can have residual neutropenia (<1 x 10^9/L) or thrombocytopenia (<100 x 10^9/L).

    Measured: Assessed every 3 months for the first 2 years and then every 6 months until relapse or death up to 3 years from registration.

Secondary outcomes (1)

  1. The Rate of Treatment Failure

    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

    Measured: Assessed every 3 months for the first 2 years and then every 6 months until relapse or death up to 3 years from registration.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted12 Mar 2008 (estimated)
  2. Study startOct 2008
  3. Primary completionSep 2014
  4. Study completionOct 2014

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
92 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00634244
Sponsor's protocol ID
NCI-2009-00520
Other IDs
NCI-2009-00520, E1906, U10CA021115
Status last verified
Apr 2015
First submitted
11 Mar 2008
Last updated
7 Jul 2015
Data monitoring committee
No

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing alvocidib, mitoxantrone hydrochloride and carboplatin in people with Adult Acute Megakaryoblastic Leukemia (M7) and Adult Acute Minimally Differentiated Myeloid Leukemia (M0), run by National Cancer Institute (NCI) at 20 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 29 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 7 Jul 2015. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 20 sites in United States, Israel. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 7 Jul 2015). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

The Rate of Complete Remission (CR+CRi) (time frame: Assessed every 3 months for the first 2 years and then every 6 months until relapse or death up to 3 years from registration.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00634244.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Jul 2015; AzTrials last refreshed its copy on 1 Nov 2026.

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