RAD001 in Combination With PKC412 in Patients With Relapsed, Refractory or Poor Prognosis AML or MDS

- This is a dose-escalation study in which 3 participants will be given a particular
starting dose of RAD001 on a certain schedule. If the dose and schedule are well
tolerated, then the next 3 participants enrolled will be assigned a new dosing schedule
and/or a higher dose of RAD001. This will continue until a maximum tolerated dose (MTD)
is reached for RAD001.

- Each cycle of treatment consists of 28 days on an outpatient basis. Participants will
receive RAD001 as the assigned schedule and dosage on day 1 and on days 8 through 28 for
the first cycle. For all subsequent cycles RAD001 will be taken once daily.
Additionally, all participants will take PKC412 twice a day on days 2 through 28 for the
first cycle. For all subsequent cycles PKC412 will be taken twice daily.

- During the course of the trial the following evaluations and procedures will be
completed at various times: review of medical history; review of concomitant
medications; physical exam; performance status; vital signs; EKG; chest x-ray; blood
tests and bone marrow aspirate/biopsy.

Inclusion Criteria:

- Cytopathologically or histopathologically confirmed diagnosis of AML, MDS (RAEB-1, -2)
or CMML, who are either relapsed or refractory to standard therapy, or are considered
inappropriate candidates for standard therapy.

- Inappropriateness for standard therapy requires a) MDS patients: not be a candidate
for immediate allogeneic stem cell transplantation, not have a -5q-cytogenetic
abnormality (unless previously received lenalidomide), and not be an appropriate
candidate for a DNA hypomethylating agent b) AML patients must be 60 years of age or
greater and have one of more of the following documented poor risk factors: ECOG
Performance Status = 2, 70 years of age or older, unfavorable cytogenetics.

- Life expectancy of at least 12 weeks

- Not likely to require cytoreductive therapy within one month (other than hydroxyurea)

- ECOG Performance Status of 2 or less

- Serum transaminase activity (AST/SGOT & ALT/SGPT) < 2.5 x ULN

- Serum total bilirubin < 1.5 x ULN ( with the exception of individuals with Gilbert's
disease)

- INR < 1.3 (or < 3 on anticoagulants)

- Fasting serum cholesterol 300mg/dl or 7.75 mmol/L or less AND fasting triglycerides
2.5 ULN or less

Exclusion Criteria:

- Prior allogeneic, syngeneic, or autologous bone marrow transplant or stem cell
transplant less than 2 months previously

- Female patients who are pregnant or breast feeding or adults of child bearing not
employing double barrier contraception

- Concurrent severe and/or uncontrolled medical or psychiatric condition which may
interfere with the completion of the study

- Impairment of gastrointestinal function or GI disease that may significantly alter
absorption of PKC412 or RAD001

- Uncontrolled active infection

- Any pulmonary infiltrate on teh baseline chest x-ray known to be new in the previous 4
weeks

- Patients with a Grade 2 or higher hypercholesterolemia or hypertriglyceridemia despite
lipid-lowering therapy

- Patients with history of another malignancy within the past 5 years, with the
exception of adequately treated basal or squamous cell skin carcinoma or cervical
carcinoma in situ

- History of non-compliance to medical regimens and patients who are unwilling or unable
to comply with this protocol

- Prior treatment with any investigational drug within preceding 4 weeks

- Chronic treatment with systemic steroids or another immunosuppressive agent

- Patients should not receive immunization with attenuated live vaccines within one week
of study entry or during study period

- Any severe or uncontrolled medical conditions or other conditions that could affect
their participation

- Known history of HIV seropositivity

- Known hypersensitivity to RAD001 or other rapamycins or to its excipients

- Known hypersensitivity to PKC412 or to its excipients

- Diagnosis of acute promyelocytic leukemia