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

Information source: National Cancer Institute (NCI)
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: 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(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

Intervention: alvocidib (Drug); mitoxantrone hydrochloride (Drug); carboplatin (Drug); cytarabine (Drug); sirolimus (Drug); etoposide (Drug); topotecan hydrochloride (Drug)

Phase: Phase 2

Status: Completed

Sponsored by: National Cancer Institute (NCI)

Official(s) and/or principal investigator(s):
Mark Litzow, Principal Investigator, Affiliation: ECOG-ACRIN Cancer Research Group


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.

Clinical Details

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)

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

Primary outcome: The Rate of Complete Remission (CR+CRi)

Secondary outcome: The Rate of Treatment Failure

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.


Minimum age: 18 Years. Maximum age: 65 Years. Gender(s): Both.


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


- 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


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


- < 300 mg/m^2 of doxorubicin

- < 300 mg/m^2 of daunorubicin

- < 100 mg/m^2 of idarubicin

- < 100 mg/m^2 of mitoxantrone

Locations and Contacts

Rambam Medical Center, Haifa 31096, Israel

University of Alabama at Birmingham, Birmingham, Alabama 35294, United States

Mayo Clinic in Arizona, Scottsdale, Arizona 85259, United States

Mayo Clinic in Florida, Jacksonville, Florida 32224-9980, United States

Northwestern University, Chicago, Illinois 60611, United States

Siouxland Hematology Oncology Associates, Sioux City, Iowa 51101, United States

Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland 21287, United States

Tufts Medical Center, Boston, Massachusetts 02111, United States

Mayo Clinic, Rochester, Minnesota 55905, United States

The Jewish Hospital, Cincinnati, Ohio 45236, United States

Geisinger Medical Center, Danville, Pennsylvania 17822-2001, United States

Geisinger Medical Center-Cancer Center Hazleton, Hazleton, Pennsylvania 18201, United States

Penn State Milton S Hershey Medical Center, Hershey, Pennsylvania 17033-0850, United States

Lewistown Hospital, Lewistown, Pennsylvania 17044, United States

Geisinger Medical Group, State College, Pennsylvania 16801, United States

Mount Nittany Medical Center, State College, Pennsylvania 16803, United States

Geisinger Wyoming Valley, Wilkes-Barre, Pennsylvania 18711, United States

Vanderbilt-Ingram Cancer Center, Nashville, Tennessee 37232, United States

University of Wisconsin Hospital and Clinics, Madison, Wisconsin 53792, United States

Froedtert and the Medical College of Wisconsin, Milwaukee, Wisconsin 53226, United States

Additional Information

Starting date: October 2008
Last updated: July 2, 2015

Page last updated: August 23, 2015

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