A Phase II Trial of Perifosine in Patients with Chemo-Insensitive Sarcomas Dejka M. Steinert, MD

1. A Phase II Trial of Perifosine in Patients with Chemo-Insensitive SarcomasDejka M. Steinert, MD

2. Rationale for Study • Phase I study: 2/10 (20%) evaluable sarcoma patients responded • One patient each • Chondrosarcoma • Leiomyosarcoma • Phase I study of perifosine combined with gemcitabine: One patient with chondrosarcoma showed a 17% decrease in size of tumor after two cycles

3. Rationale for Study • In one Phase II study in sarcoma, out of 19 evaluable patients: • One PR (extra-skeletal myxoid chondrosarcoma) • Two SD

4. Rationale of Study • Two out of the three partial responses occurred in patients with sarcoma subtypes that have been previously unresponsive to conventional therapy: • Chondrosarcomas • Extraskeletal myxoid chondrosarcoma • Will include alveolar soft part sarcoma as well since response rates to standard therapy are very poor

5. Protocol Design • Phase II study of perifosine in patients with: • Chondrosarcoma • Alveolar soft part sarcoma • Extra-skeletal myxoid chondrosarcoma • Patients will receive perifosine 100 mg orally daily with food until disease progression. • Response to therapy will be based on Choi criteria

6. Objectives Primary: • To evaluate the response rate of perifosine 100 mg by mouth daily in patients with chondrosarcoma, extra-skeletal myxoid chondrosarcoma and alveolar soft part sarcoma

7. Objectives Secondary: • To determine the time to progression of perifosine 100 mg by mouth daily in patients with chondrosarcoma, extra-skeletal myxoid chondrosarcoma, and alveolar soft part sarcoma • To determine stable disease of six months or greater of perifosine 100 mg by mouth daily in the same patient population

8. Inclusion Criteria • Patients must have a diagnosis of chondrosarcoma, extra-skeletal myxoid chondrosarcoma, or alveolar soft part sarcoma • Patients may have had prior chemotherapy, but if the patient has had three or more forms of chemotherapy, the patient’s clinical coarse should be discussed with the study chairman • Patients must have progression of disease by Choi criteria • ECOG PS 0-1. Patients with a PS 2 may be admitted with approval from study chairman

9. Inclusion Criteria • At least 13 years of age • Patients must have measurable disease • Life expectancy of more than 3 months. • Normal organ and marrow function • Patients must have recovered from acute toxicity related to prior therapy including surgery or radiotherapy to a grade equal to or less than 1

10. Inclusion Criteria • Patients must be able to ingest oral medications or to obtain them through a gastrostomy tube • Female patients who are pregnant or lactating are ineligible. Negative pregnancy test within 72 hours of treatment. Patients must agree to employ adequate contraception while on therapy and for 4 weeks after completion of therapy • Patients must have the ability to understand and the willingness to sign a written informed consent document

11. Exclusion Criteria • Patients receiving therapies administered with the intent to treat the patient’s malignancies, except bisphosphonates • History of allergic reactions attributed to compounds of similar chemical or biologic composition to perifosine (miltefosine or edelfosine) • Uncontrolled intercurrent illness. Patients with a history of unstable or newly diagnosed angina pectoris, recent MI (within 6 months of enrollment) or New York Heart Association II – IV CHF

12. Treatment Plan • Perifosine is available in 50 mg tablets • Patients will take two perifosine 50 mg tablets orally once a day at bedtime with some food

13. Study Evaluations • Patients will be seen and evaluated at baseline and then once every four weeks • Evaluation for progression or response will be made at three months intervals • Responses will be recorded using both RECIST and Choi criteria • All protocol decisions will be made by the use of Choi criteria

14. Dose Modifications for Perifosine Related Toxicities • Grade 1 Toxicities: • Treatment with perifosine will not be interrupted • Grade 2 Toxicities: • Maintain dosing with symptomatic treatment • If persistent, reduce dose as follows: • If > 50 mg/day, reduce dose by 50 mg • If patient is receiving 50 mg/day and toxicity recurs, remove patient from study

15. Dose Modifications for Perifosine Related Toxicities • Grade 3 & 4 toxicities: • Hold perifosine until less than or equal to grade 1 or has returned to baseline level • If > two weeks, consult study chairman • If less than or equal to two weeks, reduce dose by 50 mg. • If patient is receiving 50 mg/day and toxicity recurs, remove patient from study

16. Statistical Considerations • Favorable outcome will be defined as a complete or partial response or stable disease for six months or longer by Choi criteria • A favorable outcome rate of 10-20% will be taken as evidence that perifosine may have clinical benefit in these subtypes • A multi-stage Bayesian design will be used to evaluate each sarcoma histology separately • Maximum sample size of 37 per each subtype; total for trial of 111

17. SARC Participants • Scott Okuno, MD • Mayo Clinic • Dennis Priebat, MD • Washington Hospital Center • Christopher Ryan, MD • Oregon Health & Science Univ. • Scott Schuetze, MD, PhD • University of Michigan • Amir Shahlee, MD • University of Florida • Arthur Staddon, MD • Pennsylvania Hem/Onc Associates • William Tap, MD • UCLA School of Medicine • Meg Von Mehren, MD • Fox Chase Cancer Center • Sant Chawla, MD • Century City Hospital • Gina D’Amatto, MD • H. Lee Moffitt Cancer Center • George Demetri, MD • Dana-Farber Cancer Institute • Michael Fanucchi, MD • Emory University • Kenneth Hande, MD • Vanderbilt University • David Harmon, MD • Massachusetts General Hospital • Lee Helman, MD • NCI-Pediatric Branch • Robert Maki, MD, PhD • Memorial Sloan Kettering Principle Investigator Dejka Steinert, MD MD Anderson Cancer Center

18. Status of Protocol • CRF Design and Content • Completed • EDC system beta testing • Oct 21 – Nov 7 • Initiation Meeting at MD Anderson: • November 9, 2006 • Activation: • Immediately following initiation meeting