A Phase 1/2 Trial of Perifosine in the Treatment of Non-Small Cell Lung Cancer

The primary purpose of Part I of this study was to determine the maximum dose of perifosine
that can be administered with tolerable gastrointestinal toxicity; and to obtain preliminary
information on the response rate of perifosine in non-small cell lung cancer. In addition,
the trial was and is designed to provide some insight into the nature of the anti-tumor
effect, the time to response, and dose-schedules that should be used in future trials.

Part 2 - In the second part of this study, patients will be randomized to one of 3
dose-schedules of perifosine and to test if the response rate of perifosine in non small cell
lung cancer is > 10% in any of the 3 arms of the study. The study is not designed to compare
the response rates in the 3 arms of the trial, but toxicities will be compared. The regimens
are:

- A weekly dose of 900 mg to be divided into three doses of 300 mg each. If patients
experience no grade 2 toxicities during their first month of therapy, the dose will be
escalated to 1,200 mg divided into four doses of 300 mg.

- A daily dose of 150 mg to be divided into three doses of 50 mg each. If patients
experience no grade 2 toxicities during their first month of therapy, the dose will be
escalated to 200 mg divided into four doses of 50 mg.

- A daily dose of 150 mg to be given in one dose at bedtime. If patients experience no
grade 2 toxicities during their first month of therapy, the dose will be escalated to
200 mg to be given in one dose at bedtime.

Patients receiving weekly perifosine will receive prophylactic antiemetics. Patients
receiving daily perifosine will not routinely receive prophylactic antiemetics unless they
experience nausea. All patients may continue therapy unless disease progression is documented
on two occasions at least 4 weeks apart. Patients who experience toxicity may continue on
treatment with doses delayed or reduced.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed diagnosis of non-small
cell lung cancer, must have progressed despite standard therapy and must not be
candidates for surgical or combined modality therapy.

- At least 18 years of age.

- Patients should have received at least one but no more than two prior chemotherapy
regimens for metastatic disease. The study chairman or medical monitor will consider
extenuating circumstances for patients with more than two such regimens.

- Patients must have measurable disease. Since the outcome for a patient is to be based
on response using RECIST criteria, the patient must have at least one measurable
lesion that can be accurately measured in at least one dimension and fit one of the
following criteria: longest diameter 20 mm using conventional techniques or 10 mm with
spiral CT scan.

- Patients must have a life expectancy of more than 3 months.

- Patients should have a performance status of 0 to 1 according to the ECOG criteria.
However, patients with ECOG performance status of 2 may be admitted with approval from
the study chairman or medical monitor.

- 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 four weeks after the
completion of treatment.

- Patients must have ability to understand and the willingness to sign a written
informed consent document.

Exclusion Criteria

- Patients with rapidly progressing disease, as defined by progression within 12 weeks
of initiation of the previous regimen.

- Patients 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).

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection and psychiatric illness/social situations that would limit compliance with
study requirements.

- HIV-positive patients receiving combination anti-retroviral therapy are excluded from
the study because of possible pharmacokinetic interactions with perifosine.

- Patients with a history of unstable or newly diagnosed angina pectoris, recent
myocardial infarction (within 6 months of enrollment) or New York Heart Assoc. class
II-IV congestive heart failure.