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Patients receive carboplatin and topotecan hydrochloride IV continuously over 24 hours on days 1-5.

Patients 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.

Patients 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)

alvocidib

mitoxantrone hydrochloride

carboplatin

cytarabine

sirolimus

etoposide

topotecan hydrochloride

Mark Litzow

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.

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.

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

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)

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).

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

National Cancer Institute (NCI)

Arm A (Carboplatin+Topotecan Hydrochloride)

Patients 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.

Arm B (Alvocidib+Cytarabine+Mitoxantrone)

Patients 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)

Arm C (Sirolimus+Mitoxantrone+Etoposide+Cytarabine)

Total

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

< 6 months after 1st CR

6-12 mos after 1st CR

Refractory

Unknown/Missing

Disease status

Study Statistician

The Rate of Complete Remission (CR+CRi)

The Rate of Treatment Failure

Patients receive carboplatin and topotecan hydrochloride IV continuously over 24 hours on days 1-5.

carboplatin: Given IV

topotecan hydrochloride: Given IV

Arm A (Carboplatin and Topotecan Hydrochloride)

Patients 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.

alvocidib: Given IV

mitoxantrone hydrochloride: Given IV

cytarabine: Given IV

Arm B (Alvocidib, Mitoxantrone Hydrochloride, Cytarabine)

Patients 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)

mitoxantrone hydrochloride: Given IV

cytarabine: Given IV

sirolimus: Given PO

etoposide: Given IV

Arm C (Mitoxantrone Hydrochloride, Cytarabine, Sirolimus)

Overall Study

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Comparing Three Different Combination Chemotherapy Regimens in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia	NCT00634244	Adult Acute Meg... Adult Acute Min... Adult Acute Mon... Adult Acute Mon... Adult Acute Mye... Adult Acute Mye... Adult Acute Mye... Adult Acute Mye... Adult Acute Mye... Adult Acute Mye... Adult Acute Mye... Adult Erythrole... Adult Pure Eryt... Recurrent Adult...	alvocidib mitoxantrone hy... carboplatin cytarabine sirolimus etoposide topotecan hydro...	18 Years - 65 Years	National Cancer Institute (NCI)
Comparing Three Different Combination Chemotherapy Regimens in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia	NCT00634244	Adult Acute Meg... Adult Acute Min... Adult Acute Mon... Adult Acute Mon... Adult Acute Mye... Adult Acute Mye... Adult Acute Mye... Adult Acute Mye... Adult Acute Mye... Adult Acute Mye... Adult Acute Mye... Adult Erythrole... Adult Pure Eryt... Recurrent Adult...	alvocidib mitoxantrone hy... carboplatin cytarabine sirolimus etoposide topotecan hydro...	18 Years - 65 Years	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for acute myelogenous leukemia (aml), carboplatin, topotecan, flavopiridol, mitoxantrone, cytosine arabinoside, sirolimus, etoposide