Inclusion Criteria

• Histologically confirmed diagnosis of Kit expressing advanced GIST. This includes patients with metastatic disease or with primary tumors that are considered inoperable.
• Patients may have "limited" (some but not all tumor foci progressing that are not amenable to local therapy) or "generalized" (widespread growth of all tumor foci) progression after adequate therapy with imatinib mesylate. Patients must have progression of disease on imatinib mesylate (at any dose greater than or equal to 300 milligrams daily).
• Patients must have documented measurable disease by CT scan (> 2 cm by conventional CT or > 1 cm by spiral CT). If a targeted lesion has been previously embolized or irradiated, there must be objective evidence of progression of the lesion per CT scan, post-embolization or in the radiated field.
• Patients must be at least four weeks out and recovered from acute toxicities of prior therapy, including radiation, biotherapy, chemotherapy or embolization (with the exception of imatinib mesylate).

• All patients must have progressive disease on imatinib defined as:

  • An increase in unidimensional tumor size of >10% and did not meet criteria for PR by CT density
  • Any new lesions, including new tumor nodules in a previously cystic tumor, while on imatinib therapy
• Patients should have a performance status of 0 to 2 according to the ECOG criteria.
• Patients must have adequate organ function, unless in the opinion of the treating investigator, the abnormality is related to tumor and the study chairman or medical monitor agree the abnormality is unlikely to affect the safety of perifosine use. Adequate organ and marrow function is described in the protocol.
• Patients must be able to ingest oral medications or to obtain them through a gastrostomy tube.
• Patients must have ability to understand and the willingness to sign a written informed consent document.
• Patients must be at least 18 years of age

Exclusion Criteria

• Presence of known symptomatic CNS metastases

• Significant concurrent medical disease other than GIST, including:

  • New York Heart Association class III or IV cardiac problems (e.g., congestive heart failure, acute myocardial infarction within 2 months of study), uncontrolled chronic renal
  • liver disease
  • uncontrolled diabetes
  • uncontrolled seizure disorder
  • active uncontrolled infection
  • organ allografts
  • psychiatric illness/social situations that would limit compliance with study requirements
• History of active secondary cancer, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the patient has been disease-free for 5 or more years.
• Patients who are receiving any other investigational agents or devices.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to perifosine (miltefosine or edelfosine).
• HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with perifosine.
• Female patients who are pregnant or lactating are ineligible. All females of childbearing potential must have a negative serum pregnancy test within 72 hours of treatment. Men and women of childbearing potential must agree to employ adequate contraception to prevent pregnancy while on therapy and for 4 weeks after the completion of treatment. Post-menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential.