Trial Information

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)

PRIMARY OBJECTIVES:

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.