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.
- 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
Last updated: 02/05/2013
NCT ID: NCT00634244