Dose Escalation Phase I/II Study of Lovastatin With High-Dose Cytarabine for Refractory or Relapsed AML

The rationale for combining lovastatin with cytosine arabinoside (HiDAC) in this trial is
based on a study in press in Leukemia Research. This study demonstrated that there are
synergistic interactions between cytosine arabinoside and lovastatin against human leukemia
cell lines. In particular, this synergistic activity was observed in MTT assay. Given that
there is such synergistic interaction in vitro it is reasonable to determine whether such
interaction occurs in vivo. The proposed trial thus uses standard doses of HiDAC with
incrementally increasing dose of lovastatin. This particular trial will follow an accelerated
titration for lovastatin. The first dose level will be lovastatin at 0.5 mg/kg/day, divided
into two daily PO doses given Q 12 hours on Days 1 -7 for a total of 14 doses. Doses should
be rounded to the nearest 20 mg. After each subject reaches day 14, subsequent subjects will
be treated at incrementally increasing doses that are 1 mg/kg/day, 2 mg/kg/day, 4 mg/kg/day,
8 mg/kg/day, 12 mg/kg/day, 18 mg/kg/day, and 24 mg/kg/day, with all doses divided into two
daily PO doses given Q 12 hours on Days 1 - 7 for a total of 14. If MTD is not reached at the
24 mg/kg/day dose level, further dose escalations will occur with a 33% increase in dose at
each level, rounded to the nearest 20 mg/kg/day.

Inclusion Criteria:

- Patients with primary refractory AML (that is no prior remission). Patients who have
greater than 10% AML blasts in the bone marrow or blood upon recovery from two cycles
of standard cytarabine- and anthracycline-based induction chemotherapy are eligible.
Patients who have received etoposide and/or 6-thioguanine during remission induction
will be eligible.

- Patients with relapsed AML. Patients must have had a documented remission lasting > 30
days at some point during their prior therapy. Their current relapse must be
untreated. Relapse is defined as the presence of greater than 10% AML blasts in the
bone marrow or blood after having had a documented remission.

- Patients who have received a high-dose cytarabine containing regimen (>2 g/m2/dose)
within 3 months prior to registration on this protocol are not eligible.

- No active CNS involvement. A lumbar puncture prior to treatment is not required and
should not be performed in the absence of significant CNS symptoms or signs.

- Non-pregnant and non-nursing. Treatment under this protocol would expose an unborn
child to significant risks. Women and men of reproductive potential should agree to
use an effective means of birth control.

Exclusion Criteria:

Although NOT considered formal Exclusion Criteria, study physicians are strongly encouraged
as part of this decision-making process to recognize that the following may increase the
risks to a subject entering this protocol:

- Other serious illnesses which would limit survival to <2 years, or a psychiatric
condition which would prevent compliance with treatment or informed consent.

- Performance Status > 2.

- Uncontrolled or severe cardiovascular disease, diabetes, pulmonary disease, or
infection, which in the opinion of the treating physician, would make this protocol
treatment unreasonably hazardous for the patient.

- Patients with a "currently active" second malignancy other than non-melanoma skin
cancers. Patients are not considered to have a "currently active" malignancy if they
have completed therapy and considered by their physician to be at less than 30% risk
of relapse within one year.

- Patients who have received any investigational agent within the prior 4 weeks.