Phase II PKC412 in Aggressive Systemic Mastocytosis and Mast Cell Leukemia

Inclusion Criteria:

• Histologically documented aggressive systemic mastocytosis or mast cell leukemia + AHNMD, regardless of the presence of absence of the D816V c-kit mutation, or the FIP1L1-PDGFR alpha fusion.
• Tissue for evaluation of KIT mutation status of the tumor cells must be collected and availability confirmed by PI within 6 months prior to entry into study (e.g. wild-type, D816V, or other KIT mutation). Patients who have systemic mastocytosis with eosinophilia and known positivity for the FIP1L1-PDGFR alpha fusion are also eligible only if they have demonstrated relapse or disease progression on prior imatinib therapy.
• Karnofsky performance status of >30%.
• Liver enzyme values within normal limits unless the sole cause of liver elevation is due to ASM/MCL. Else, patients must have the following laboratory values: AST and ALT <= 4X ULN, and/or bilirubin <= 4X ULN if elevation of liver enzymes is considered solely due to ASM/MCL.
• Serum creatinine <2.0 mg/dL
• For patients with grade >2 blood values, the screening bone marrow exam (e.g. presence of mast cell infiltrate as defined in Appendix B) and/or the presence of disease-related hypersplenism should establish that the likely causes of these cytopenia(s) is related to ASM/MCL.
• No clinical or radiographic (by PA and lateral chest x-ray) evidence of active pulmonary disease which is considered by the investigator to be unrelated to mastocytosis.
• Patient must give written informed consent.

Exclusion Criteria:

• Female patients who are pregnant or breast-feeding, or any adult, male or female, of reproductive potential not agreeing to employ barrier contraceptives throughout the study.
• Women of childbearing potential must have a negative serum pregnancy test 48 hours prior to administration of study drug, are required to use barrier contraception for the duration of the study and for 3 months post study because of the long half life of the metabolite, CGP52421, and must avoid breast-feeding.
• Any other known disease, concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, cardiovascular disease including congestive heart failure, myocardial infarction within 6 months, any Grade 3/4 cardiac problems as defined by the New York Heart Association Criteria and poorly controlled hypertension, chronic renal disease, active uncontrolled infection) which could compromise participation in the study.
• Known confirmed diagnosis of HIV infection or active viral hepatitis.
• Patients who have received any investigational agent, chemotherapy, or 2-chlorodeoxyadenosine (2-CdA) within 30 days prior to Day 1 of PKC412 treatment.
• Patients who have received interferon-alpha within 30 days prior to Day 1 of PKC412 treatment.
• Patients who have received hematopoietic growth factor support within 14 days of Day 1 of PKC412 treatment.
• Glucocorticoids should be tapered off within 14 days of Day 1 of PKC412 treatment if it is anticipated that patients can be tapered off these drugs. Otherwise, for glucocorticoid-requiring patients, investigators should attempt to taper to the minimal dose possible at the time of PKC412 start on day 1.
• Patients who have had any surgical procedure, excluding central venous catheter placement or other minor procedures (e.g. skin biopsy) within 14 days of Day 1 of PKC412 treatment.
• Patients unwilling or unable to comply with the protocol.
• Patients with known malignant disease involving the central nervous system.
• Patient with any pulmonary infiltrate or abnormality on the baseline chest X-ray known to be new in the previous 4 weeks. However, if a patient has a pleural effusion which is considered related to systemic mastocytosis (e.g. secondary to ascites) and not causing symptomatic respiratory complaints, the patient may be eligible after discussion with the sponsor.