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Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic SyndromePhase 2NCT01349972

Alvocidib, Cytarabine, and Mitoxantrone Hydrochloride or Cytarabine and Daunorubicin Hydrochloride in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia

A Phase 2 study testing alvocidib, daunorubicin hydrochloride and mitoxantrone hydrochloride in people with Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome and Adult Acute Minimally Differentiated Myeloid Leukemia (M0), run by National Cancer Institute (NCI) at 11 sites in United States.

Completed

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

Official record
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Trial summary

This randomized phase II trial is studying how alvocidib, cytarabine, and mitoxantrone hydrochloride work compared to cytarabine and daunorubicin hydrochloride in treating patients with newly diagnosed acute myeloid leukemia. Read more about this study

Who is it for?
Ages 18 to 70 years
What is being tested?
alvocidib, daunorubicin hydrochloride and mitoxantrone hydrochloride
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
172 participants
Where
11 sitesUnited States
Study dates
Apr 2011to May 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 70 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • All adults with established, pathologically confirmed diagnoses of newly diagnosed AML and adults with newly diagnosed AML, excluding newly diagnosed core-binding factor (CBF) AMLs and acute progranulocytic leukemia (APL, M3), will be considered eligible for study
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-3
  • Patients >= 65 years of age must have ECOG PS =< 2 prior to developing leukemic symptoms
  • Serum creatinine ≤ 2.0 mg/dL
  • Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =< 5 times upper limit of normal (ULN) (unless leukemic infiltration)
  • Total bilirubin =< 2.0 mg/dL (unless Gilbert disease, hemolysis, or leukemia)
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  • Left ventricular ejection fraction ≥ 45%
  • Newly diagnosed AML, subtypes M0, 1, 2, 4-7 but excluding M3 (APL), including those with the following poor risk features:
  • Antecedent hematologic disorder including myelodysplasia (MDS)-related AML (MDS/AML) and prior myeloproliferative disorder (MPD)
  • Treatment-related myeloid neoplasms (t-AML/t-MDS)
  • Myeloid sarcoma, myeloid proliferations related to Down Syndrome, and blastic plasmacytoid dendritic cell neoplasm
  • AML with multilineage dysplasia (AML-MLD)
  • Adverse cytogenetics (defined as -5/-5q; -7/-7q; abnormal 3q, 9q, 11q, 20q, 21q, or 17p; t(6;9); t(9;22); trisomy 8; trisomy 13; trisomy 21; and complex karyotypes (≥ 3 unrelated abnormalities)
  • Patients who have received hydroxyurea alone or have received non-cytotoxic therapies previously for myelodysplasia (MDS) or myeloproliferative disorder (MPD) (e.g., thalidomide or lenalidomide, interferon, cytokines, 5-azacytidine or decitabine, histone deacetylase inhibitors, low-dose cyclophosphamide [cytoxan], tyrosine kinase [TK] or dual TK/src inhibitors) will be eligible for this trial
  • At least 24 hours since prior leukopheresis or hydroxyurea for cytoreduction

Who cannot join

  • Any previous treatment with flavopiridol
  • Concomitant chemotherapy, radiation therapy, or immunotherapy
  • Hyperleukocytosis with >= 50,000 blasts/uL; leukopheresis or hydroxyurea may be used immediately prior to study drug administration for cytoreduction; must be stopped 24 hours before first dose of study chemotherapy
  • CBF AMLs associated with t(8;21) or M4eo subtype (inv[16] or t[16;16]), as diagnosed by morphologic criteria, flow cytometric characteristics, and rapid cytogenetics or FISH or molecular testing
  • Acute Progranulocytic Leukemia (APL, M3)
  • Active central nervous system (CNS) leukemia
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  • Active, uncontrolled infection; patients with infection under active treatment and controlled with antibiotics are eligible
  • Active, uncontrolled graft vs. host disease (GVHD) following allogeneic transplant for non-AML condition (e.g. MDS, lymphoid malignancy, aplastic anemia); patients with GVHD controlled on stable doses of immunosuppressants are eligible
  • Presence of other life-threatening illness
  • Patients with mental deficits and/or psychiatric history that preclude them form giving informed consent or from following protocol
  • Pregnant and nursing patients are excluded

Trial locations and contacts

11 sites in 1 country.

11 sites in 1 country

United States11 sites

  • Blood and Marrow Transplant Group of Georgia

    Atlanta, Georgia, 30342

  • University of Maryland/Greenebaum Cancer Center

    Baltimore, Maryland, 21201

  • Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center

    Baltimore, Maryland, 21287

  • University of North Carolina

    Chapel Hill, North Carolina, 27599

  • University of Chicago

    Chicago, Illinois, 60637

  • Baylor University Medical Center

    Dallas, Texas, 75246

  • Vanderbilt-Ingram Cancer Center

    Nashville, Tennessee, 37232

  • Virginia Commonwealth University

    Richmond, Virginia, 23298

  • Mayo Clinic

    Rochester, Minnesota, 55905

  • Mayo Clinic Scottsdale-Phoenix

    Scottsdale, Arizona, 85259

  • Moffitt Cancer Center

    Tampa, Florida, 33612

Other trials in United States

About this study

Official title: Randomized Phase II Trial of Timed Sequential Therapy (TST) With Alvocidib (Flavopiridol), Ara-C and Mitoxantrone (FLAM) vs. "7+3" for Adults Age 70 and Under With Newly Diagnosed Acute Myelogenous Leukemia (AML)

This randomized phase II trial is studying how alvocidib, cytarabine, and mitoxantrone hydrochloride work compared to cytarabine and daunorubicin hydrochloride in treating patients with newly diagnosed acute myeloid leukemia. Alvocidib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cytarabine, mitoxantrone hydrochloride, and daunorubicin hydrochloride work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. It is not yet known whether giving alvocidib, cytarabine, and mitoxantrone hydrochloride is more effective than giving cytarabine and daunorubicin hydrochloride in treating patients with acute myeloid leukemia.

Read the detailed description

PRIMARY OBJECTIVES:

  1. To compare the rate of complete remission (CR) after 1 course of induction therapy with the timed-sequential combination of alvocidib (flavopiridol), cytarabine (cytosine arabinoside [ara-C]), and mitoxantrone hydrochloride (FLAM) vs traditional "7+3" cytarabine and daunorubicin hydrochloride (ara-C + Daunorubicin) for adults (age 18 to 70) with newly diagnosed, previously untreated, intermediate-risk or poor-risk acute myelogenous leukemia (AML).

SECONDARY OBJECTIVES:

  1. To evaluate and compare the toxicities of FLAM vs 7+3. II. To compare the 2-year disease-free survival (DFS) and overall survival (OS) in response to FLAM vs 7+3.

III. To detect and compare the presence of minimal-residual disease (MRD) remaining after FLAM vs 7+3.

IV. To determine the expression of ABC transport proteins multidrug resistance 1 (MDR1, ABCB1) and breast cancer resistance protein (BCRP, ABCG2) on AML blasts pretreatment and correlate the expressions of one or both proteins with CR and DFS in response to FLAM vs 7+3.

OUTLINE: This is a multicenter study. Patients are stratified according to risk features: age (< 50 vs >= 50), secondary AML (pre-existing myelodysplatic syndrome [MDS], myeloproliferative diseases [MPD], treatment-related [t]-AML, or severe multi-lineage dysplasia) and/or known adverse cytogenetics, and hyperleukocytosis (white blood cells [WBC] >= 50,000/mm^3). Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive alvocidib intravenously (IV) over 1 hour on days 1-3, cytarabine IV over 72 hours on days 6-8, and mitoxantrone hydrochloride IV over 1-2 hours on day 9. Patients who achieve complete or partial response to the first course (completion of all doses) may receive a second course of treatment or high-dose cytarabine after 21-63 days following blood count recovery, and/or undergo allogeneic bone marrow transplant.

ARM II: Patients receive cytarabine IV continuously on days 1-7 and daunorubicin hydrochloride IV on days 1-3. Patients who have residual disease on day 14 may receive additional cytarabine for 5 days and daunorubicin hydrochloride for 2 days. Patients may undergo blood and bone marrow collection for correlative studies.

After completion of study therapy, patients are followed up every 3 months for 2 years, every 6 months for 5 years, and then annually thereafter.

Being tested
alvocidib, daunorubicin hydrochloride, mitoxantrone hydrochloride, cytarabine
Medical subject headings
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

  • daunorubicin hydrochlorideDrug

    Also called Cerubidin, Cerubidine, daunomycin hydrochloride, daunorubicin

    Given IV

  • mitoxantrone hydrochlorideDrug

    Also called CL 232315, DHAD, DHAQ

    Given IV

  • cytarabineDrug

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

    Given IV

Study groups in NCT01349972
Study groupRoleWhat they receive
Arm I (alvocidib, cytarabine, mitoxantrone hydrochloride)ExperimentalPatients receive alvocidib IV over 1 hour on days 1-3, cytarabine IV over 72 hours on days 6-8, and mitoxantrone hydrochloride IV over 1-2 hours on day 9. Patients who achieve complete or partial response to the first course (completion of all doses) may receive a second course of treatment or high-dose cytarabine after 21-63 days following blood count recovery, and/or undergo allogeneic bone marrow transplant.
Receives: Drug: alvocidib; Drug: mitoxantrone hydrochloride; Drug: cytarabine
Arm II (cytarabine, daunorubicin hydrochloride)Active comparatorPatients receive cytarabine IV continuously on days 1-7 and daunorubicin hydrochloride IV on days 1-3. Patients who have residual disease on day 14 may receive additional cytarabine for 5 days and daunorubicin hydrochloride for 2 days.
Receives: Drug: daunorubicin hydrochloride; Drug: cytarabine

What is being measured

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

  1. Complete Response Rate

    Bone marrow showing less than 5% myeloblasts with normal maturation of all cell lines, an ANC of at least 1000/cu mm and a platelet count of 100,000/cu mm, absence of blast in peripheral blood, absence of identifiable leukemic cells in the bone marrow, clearance of disease-associated cytogenetic abnormalities, and clearance of any previously existing extramedullary disease. These criteria are taken from Dohner H, Estey EH, Amadori S, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 2010;115:453-474

    Measured: 3 years

Secondary outcomes (5)

  1. Incidence of Toxicities, Characterized by Number of Events by Treatment and Grade

    The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting.

    Measured: Up to 14 days after completion of study treatment

  2. Disease-free Survival

    Probabilities will be estimated with the Kaplan-Meier estimate. Survival estimates at two years will be estimated. Disease-free survival Overall survival was defined from date of randomization to death or last known follow-up. Event free survival was defined as date of randomization to the first occurrence of persistent AML after 1 cycle of induction, relapse or death. Patients were censored for event free survival if they had received non-protocol therapy or a stem cell transplant.

    Measured: Time from randomization until death from any cause or relapse or recurrence, assessed up to 2 years

  3. Overall Survival

    Probabilities will be estimated with the Kaplan-Meier estimate. Survival estimates at two years will be estimated.

    Measured: 4 years

  4. Number of Patients With Minimal Residual Disease

    Comparisons of the treatments with respect to MRD will be based on the number of patients with MRD at day 14 after the start of treatment.

    Measured: From study start to 14 days after the start of treatment

  5. Progression-free Survival

    Probabilities will be estimated with the Kaplan-Meier estimate. Survival estimates at two years will be estimated.

    Measured: 4 years

Timeline

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

  1. First posted9 May 2011 (estimated)
  2. Study startApr 2011
  3. Primary completionMay 2014
  4. Study completionMay 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
172 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01349972
Sponsor's protocol ID
NCI-2011-02587
Other IDs
NCI-2011-02587, JHOC-J1101, CDR0000699421, J1101, 8972, U01CA070095, N01CM00100, P30CA006973
Status last verified
Jul 2017
First submitted
6 May 2011
Last updated
31 Jul 2017

Publications

  • Zeidner JF, Foster MC, Blackford AL, Litzow MR, Morris LE, Strickland SA, Lancet JE, Bose P, Levy MY, Tibes R, Gojo I, Gocke CD, Rosner GL, Little RF, Wright JJ, Doyle LA, Smith BD, Karp JE. Randomized multicenter phase II study of flavopiridol (alvocidib), cytarabine, and mitoxantrone (FLAM) versus cytarabine/daunorubicin (7+3) in newly diagnosed acute myeloid leukemia. Haematologica. 2015 Sep;100(9):1172-9. doi: 10.3324/haematol.2015.125849. Epub 2015 May 28.

    PubMed 26022709

  • Gerber JM, Zeidner JF, Morse S, Blackford AL, Perkins B, Yanagisawa B, Zhang H, Morsberger L, Karp J, Ning Y, Gocke CD, Rosner GL, Smith BD, Jones RJ. Association of acute myeloid leukemia's most immature phenotype with risk groups and outcomes. Haematologica. 2016 May;101(5):607-16. doi: 10.3324/haematol.2015.135194. Epub 2016 Jan 27.

    PubMed 26819054

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing alvocidib, daunorubicin hydrochloride and mitoxantrone hydrochloride in people with Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome and Adult Acute Minimally Differentiated Myeloid Leukemia (M0), run by National Cancer Institute (NCI) at 11 sites in United States.

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 15 inclusion and 11 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 31 Jul 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 11 sites in United States. 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 6 Jun 2017). 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?

Complete Response Rate (time frame: 3 years). 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 NCT01349972, which also lists 2 linked publications.

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 31 Jul 2017.

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