1. A PHASE II TRIAL OF PERIFOSINE IN PATIENTS WITH CHEMO-INSENSITIVE SARCOMAS A SARCOMA ALLIANCE FOR RESEARCH THROUGH COLLABORATION (SARC) STUDY Study Update – November 2007 Joseph Ludwig, MD MD Anderson Cancer Center, Houston, TX

2. Background & Rationale for Perifosine Preclinical: Suspected interference with the plasma membrane (Leishmaniasis) NCI (Evaluate first on PC-3 (mut PTEN) hyperactivated PI3K/Akt): reduced (p) Akt Blocked effects in insulin, EGF, PDGF Blocked localization of Akt to plasma membrane Phase I Studies: Single agent, 2 of 10 (20%) of sarcoma patients responded (1 CS, 1 LMS) With Gemcitabine 1 patient with CS had 17% reduction in tumor size. Phase II Studies (Single agent): Mayo Clinic Phase II consortium - 1 PR (extra-skeletal myxoid) of 22 patients with STS The responses in a chondrosarcoma and a myxoid-chondrosarcoma are particularly notable because these tumors do not usually respond to cytotoxic chemotherapy Perifosine (NSC 639996)

3. Phase I Trials Sarcoma Responder - Wisconsin After 12 mo’s of 50 mg perifosine  52% decrease in size Van Ummersen et. al., Clinical Cancer Research, Vol. 10, Nov 15, 2004

4. Patients with < 2 forms of prior chemotherapy stratified by Evaluate q 3 months Progression Perifosine 100 mg qhs daily Remove From Study CR, PR, or SD Continue On Study Conventional Chondrosarcoma Extra-Skeletal Myxoid Chondrosarcoma Alveolar Soft Part Sarcoma P.S. (0-1) & Measurable, Progressive disease (Choi)

5. Objectives Primary –Evaluate the response rate defined by both Choi and RECIST criteria of single agent perifosine Secondary –Evaluate Time to Progression (TTP) –Evaluate the Clinical Benefit Rate (CR & PR + SD) –Continue to Monitor Drug Safety

6. Major Inclusion / Exclusion Inclusion –Measurable Disease –Age > 13 years –** Documented progression by Choi Criteria Exclusion –> 2 prior cytotoxic regimens for metastatic disease (unless exempted)

7. Study Population – 59 Patients Gender: 35 Male / 24 Female Median age: 51 (range 20 – 85) Cycles on Treatment (1 – 9 cycles)

8. Protocol 214 – Toxicity N = 43 Perifosine 100 mg Daily Number of Events Grade Side Effect123 Nausea1462 Vomiting861 Diarrhea1740 Anorexia520 Dyspepsia310 Stomach cramps110 Decreased hemoglobin410 Fatigue811 Dyspnea201 Photosensitivity200 Common Perifosine Events

9. Evaluate q 12 weeks Progression Perifosine 100 mg qhs daily Remove From Study CR, PR, or SD Continue On Study Conventional Chondrosarcoma Extra-Skeletal Myxoid Chondrosarcoma Alveolar Soft Part Sarcoma Measurable progressive disease (Choi) 33 11 15 59 enrolled Enrollment Status since Nov. 28 th, 2006; 12 sites open Off Study 10 3117

10. Current Enrollment Status TotalEvaluable* PR (Choi) N (%) SD (> 12 wks) N (%) Off Study Progression Off Study Other Chondro 33251 (4%)5 (20%)10(40%)7 Extra-skeletal Myxoid 15132 (15%)5 (38%)6(46%)0 Alveolar Soft Part 11103 (30%) 1(10%)3 Total 59486 (13%)13 (27%)17(35%)10 * Evaluable: Pts receiving > 1 cycle of treatment All cohorts have met criteria for full enrollment – 37 pts per arm Clinical Benefit Rate = 40%

11. Responses 1) 35 y/o female with ASPS Perifosine toxicities to date: Grade 2 Nausea / Vomiting / Diarrhea / Fever Target Lesion: Right Manubrium Baseline scan: 166.60 HU 3 mo scan: 129.60 HU 22% PR by Choi (SD by RECIST) 3) 69 y/o female with Conventional CS Perifosine toxicities to date: –Well tolerated with limited toxicity Sum of Lesions: Baseline scan: 185 HU 3 mo scan: 120 HU 6 mo scan: Pending 35.2% PR by Choi (SD by RECIST) 2) 29 y/o female with ASPS Perifosine toxicities to date: Grade 2 Nausea / Vomiting / Abd. Pain Sum of Lesions: Baseline scan: 182.80 HU 3 mo scan: 146 HU 6 mo scan: 146 HU 20.13% PR by Choi (SD by RECIST)

12. Response Criteria Difficulties Unable to obtain HU’s on a few patients Negative HU’s on one patient Eligibility Exceptions Five patients had > 3 prior chemo regimens One patient came off tx for 6 weeks for surgery and now back on after an initial response

13. Interim Conclusions Generally well tolerated –Common AE’s = GI related and fatigue Criteria met to proceed to full study enrollment Activity: Clinical Benefit (SD > 12 weeks) –Overall: 40% (19/48) Chondro: 24% (PR = 4% by Choi) ESMS: 54% (PR = 15% by Choi) ASPS: 60% (PR = 30% by Choi) Chondrosarcoma arm almost complete –33 enrolled –4 patients being screened

14. Questions Is the response rate of these sarcoma subtypes adequate to justify further study? What is the Mechanism of action. Does stable disease serve as a valid surrogate for improved survival.

15. Participants (12) / Enrollment (59) MD Anderson – 13 –Dejka Araujo, MD Penn – 12 –Arthur Staddon, MD Sarcoma Oncology – 11 –Sant Chawla, MD MSKCC - 8 –Robert Maki, MD Michigan - 5 –Scott Schuetze, MD Mass General – 5 –Edwin Choy, MD Fox Chase – 2 –Margaret von Mehren, MD Washington Cancer – 2 –Dennis Priebat, MD OHSU – 1 –Christopher Ryan, MD Others Open: DFCI, Moffitt, UFL Extra-Skeletal Myxoid Chondrosarcoma - 15 Conventional Chondrosarcoma - 33 Alveolar Soft Part Sarcoma - 11

16. Increased reliance upon imaging 0 3 6 9 12 15 Tumor Size Estimated *** Actual Calculated delta