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