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Joseph Ludwig, MD MD Anderson Cancer Center, Houston, TX

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. Background & Rationale for Perifosine. Perifosine (NSC 639996).

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Joseph Ludwig, MD MD Anderson Cancer Center, Houston, TX

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  1. A PHASE II TRIAL OF PERIFOSINE IN PATIENTS WITH CHEMO-INSENSITIVE SARCOMASA 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 Perifosine (NSC 639996) 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

  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 Conventional Chondrosarcoma Extra-Skeletal Myxoid Chondrosarcoma Alveolar Soft Part Sarcoma P.S. (0-1) & Measurable, Progressive disease (Choi) Perifosine 100 mg qhs daily Evaluate q 3 months CR, PR, or SD Progression Continue On Study Remove From Study

  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 – ToxicityN = 43 Perifosine 100 mg Daily Common Perifosine Events

  9. 33 15 11 59 enrolled 10 31 17 Conventional Chondrosarcoma Extra-Skeletal Myxoid Chondrosarcoma Alveolar Soft Part Sarcoma Measurable progressive disease (Choi) Perifosine 100 mg qhs daily Evaluate q 12 weeks Off Study CR, PR, or SD Progression Continue On Study Remove From Study Enrollment Status since Nov. 28th, 2006; 12 sites open

  10. Current Enrollment Status Clinical Benefit Rate = 40% * Evaluable: Pts receiving > 1 cycle of treatment All cohorts have met criteria for full enrollment – 37 pts per arm

  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. 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 Participants (12) / Enrollment (59) Extra-Skeletal Myxoid Chondrosarcoma - 15 Conventional Chondrosarcoma - 33 Alveolar Soft Part Sarcoma - 11

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

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