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AP23573: Potent mTOR Inhibitor

Updated interim results of a phase 2 study of the mTOR inhibitor AP23573 in patients (pts) with advanced sarcomas of soft tissue or bone Sant P. Chawla, Anthony W. Tolcher, Kamalesh K. Sankhala, Arthur P. Staddon, Camille L. Bedrosian, and George D. Demetri for the AP23573 Sarcoma Study Group

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AP23573: Potent mTOR Inhibitor

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  1. Updated interim results of a phase 2 study of the mTOR inhibitor AP23573 in patients (pts) with advanced sarcomas of soft tissue or bone Sant P. Chawla, Anthony W. Tolcher, Kamalesh K. Sankhala,Arthur P. Staddon, Camille L. Bedrosian, and George D. Demetri for the AP23573 Sarcoma Study Group 20 November 2005 CTOS 10th Annual Meeting Boca Raton, FL

  2. mTOR (FRBDomain) FKBP AP23573: Potent mTOR Inhibitor • Stable, non-prodrug rapamycin analog • Forms complex with mTOR • Low levels potently inhibit mTOR activity • Can be given i.v. or orally Metcalf CA et al. (2004) Proc Am Assoc Cancer Res 45:2476 CTOS Annual Meeting

  3. Background – AP23573 for Sarcoma • Clinical rationale – AP23573 phase 1 trial results • Six of 7 sarcoma patients (pts) treated were progression-free at 6 months – all dose levels tested • Best response (RECIST) for sarcoma pts (one each) • PR – Carcinosarcoma (on study >2.5 yrs) • MR – GIST, Ewing’s sarcoma, Liposarcoma (on study >1 yr) • SD – Leiomyosarcoma, Ewing’s sarcoma Mita M, et al. (2004) Proc Eur J Cancer 40A, Abst. #409 CTOS Annual Meeting

  4. Trial Objectives – Phase 2 • Primary • Clinical-benefit response • RECIST guidelines • CR or PR • SD ≥ 4 months • Positive outcome defined as clinical-benefit response per cohort > 25% (CR=complete response; PR=partial response; SD=stable disease) CTOS Annual Meeting

  5. Trial Design • Open label, non-randomized, fixed-dose trial • 12.5 mg i.v., QDx5 schedule • Four parallel histological cohorts • Simon’s two-stage design within each cohort • At least 4/19 pts with clinical benefit (Stage 1) • Each cohort expands to at least 44 pts (Stage 2) CTOS Annual Meeting

  6. Sarcoma Subtype Stage 1 Stage 2 Total Bone Sarcoma 21 30 51 Leiomyosarcoma 20 37 57 Liposarcoma 20 (1) 22 (1), (2) 42 Other Soft-tissue 21 41 (3) 62 Total 82 130 212 Trial Progress by Cohort Stage 1 and Stage 2recruitment complete Footnotes: (1)One pt not dosed; (2)Six pts in screening; (3)Two pts not dosed (Data as of 07Nov2005) CTOS Annual Meeting

  7. Main Eligibility Criteria • Age ≥ 15 years • ECOG performance status 0 – 1 • Adequate renal/liver function • Serum cholesterol ≤ 350 mg/dL and triglycerides ≤ 400 mg/dL • No restriction on the number of prior therapies(no prior mTOR inhibitors) • At least one measurable lesion CTOS Annual Meeting

  8. Patient Characteristics • Total number of patients enrolled 212 • Median age in years (range) 51 (17-79) • Gender (Male/Female) 103/109 • Prior chemotherapy regimens for advanced, metastatic disease Percent * • 0 12 • 1 27 • 2-3 39 • > 4 23 * 83 Patients with data available as of this analysis CTOS Annual Meeting

  9. Confirmed Partial Response with AP23573 Confirmed Partial Response7 months Baseline CTOS Annual Meeting

  10. Sarcoma Subtype No. of Pts(1) Clinical Benefit (2) Rate Bone Sarcoma 21 8(†) 38% Leiomyosarcoma 20 10 50% Liposarcoma 19 4 21% Other Soft-tissue 21 5 (‡) 24% Total 81 27 33% Clinical-benefit Response Rates – Stage 1 (†)3-PR’s; (‡) 1-PR Footnotes: (1)One pt not dosed; (2)Based on RECIST guidelines CTOS Annual Meeting

  11. Sarcoma Subtype Evaluable Pts (1) Clinical Benefit (2) Rate Bone Sarcoma 28 6 21% Leiomyosarcoma 36 10 28% Liposarcoma 5 0 0% Other Soft-tissue 38 8 21% Total 107 24 22% Early Clinical-benefit Response Rates – Stage 2 Footnotes: (1)Three pts not dosed, 20 pts too early; (2)Based on RECIST guidelines CTOS Annual Meeting

  12. AP23573 – Overall Activity in Sarcoma (Data as of 07Nov2005) CTOS Annual Meeting

  13. Historical Context for Sarcoma Footnotes: (1) Stage 1 patients (81 dosed); (2)Van Glabbeke, M et al. (2002) Eur J Cancer 38:543 CTOS Annual Meeting

  14. Day 1 (Baseline) Day 5 Day 54 CT Scan PET Scan SUVmax = 2.8 SUVmax = 1.4 SUVmax =15.1 Rapid Inhibition of Tumor Metabolism by AP23573 CTOS Annual Meeting

  15. Day 1 (Baseline) Day 5 Day 56 PET Scan Evidence of Tumor Necrosis with AP23573 CTOS Annual Meeting

  16. 24 y/o with high-grade epithelioid sarcoma with extensive lymphadenopathy Stable disease as of 4 mos Approximately 75% tumor necrosis No tumor identified in lymph nodes Patient With Epithelioid Sarcoma CTOS Annual Meeting

  17. Lymph Node Showing No Tumor CTOS Annual Meeting

  18. Definitions for PET Response* • Complete Metabolic Response: Normalization of SUVmax • Partial Metabolic Response: >25% decrease in SUVmax • Stable Metabolic Response: <25% change in SUVmax (+/-) • Increased Metabolic Response: >25% increase in SUVmax *Criteria per EORTC PET Study Group (Eur J. Cancer 1999; 35; 1773-1782) CTOS Annual Meeting

  19. PET Response Results Sankhala KK, et al. (2005) CTOS Abst #488 CTOS Annual Meeting

  20. Serious Adverse Events Considered Related CTOS Annual Meeting

  21. Adverse Events Considered Related Pts with available AE data at the time of this analysis (24Oct2005) AEs are those reported for 6 or more pts CTOS Annual Meeting

  22. Conclusions – AP23573 in Sarcoma • Compelling single-agent activity • Achieved primary objective • 27% overall clinical-benefit response • 22% preliminary 6-month PFS rate in stage 1 • Well-tolerated with manageable side-effects • Recruitment complete; follow-up and analyses ongoing • Further studies planned • As single-agent • In combination with chemotherapy CTOS Annual Meeting

  23. Acknowledgement The AP23573 Sarcoma Study Group • George D. Demetri, MD – Dana Farber Cancer Institute, Boston, MA • Arthur P. Staddon, MD – Pennsylvania Hematology Oncology Associates, Philadelphia, PA • Gina Z. D’Amato, MD – H. Lee Moffitt Cancer Center, Tampa, FL • Anthony W. Tolcher, MD – Center Therapy and Research Center, Institute for Drug Development, San Antonio, TX • Scott Schuetze, MD, PhD – University of Michigan Cancer Center, Ann Arbor, MI • Jean-Yves Blay, MD – Centre Leon Berard, Lyon, FRANCE • Warren A.Chow, MD – City of Hope National Medical Center, Duarte, CA • Gerald Edelman, MD – Mary Crowley Medical Research Center, Dallas, TX • Joseph O. Moore, MD – Duke University Medical Center, Durham, NC • David I. Quinn, MD,PhD – USC/Norris Comprehensive Cancer Center, Los Angeles, CA • Patrick Schöffski, MD, PhD – UZ Gasthuisberg, Leuven, BELGIUM • Anthony Elias, MD - University of Colorado Health Science Center, Aurora, CO • Joseph Germinio, MD – Cancer Institue of New Jersey, New Brunswick, NJ • Margaret von Mehren, MD – Fox Chase Cancer Center, Philadelphia, PA • Axel LeCesne, MD – Institut Gustave Roussy, Villejuif, FRANCE • Samir Undevia, MD – University of Chicago, Chicago, IL CTOS Annual Meeting

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