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Rationale

A Phase II Randomized Controlled Trial of Palifosfamide Plus Doxorubicin vs. Doxorubicin In Patients with Soft Tissue Sarcoma (PICASSO).

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Rationale

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  1. A Phase II Randomized Controlled Trial of Palifosfamide Plus Doxorubicin vs. Doxorubicin In Patients with Soft Tissue Sarcoma (PICASSO) C. F. Verschraegen, S. P. Chawla, M. M. Mita, C. W. Ryan, L. J. Blakely, V. L. Keedy, A. Santoro, J. Y. Buck, R. G. Maki, J. J. Lewis, and PICASSO Study Investigators University of New Mexico Cancer Center, Albuquerque, NM; Sarcoma Oncology Center, Santa Monica, CA; Cancer Therapy & Research Center, San Antonio, TX; Oregon Health & Science University Cancer Institute, Portland, OR; West Clinic, Memphis, TN; Vanderbilt Univ, Nashville, TN; Istituto Clinico Humanitas, Milano, Italy; ZIOPHARM Oncology, Inc, Boston, MA; Memorial Sloan-Kettering Cancer Center, New York, NY

  2. Rationale • Palifosfamide-tris, a novel, bi-functional DNA cross-linker, is the stabilized active metabolite of ifosfamide • Palifosfamide has broad activity against human sarcoma cell lines in vitro and in human xenografts, including in ifosfamide- and cyclophosphamide-resistant xenograft tumors • Mesna administration is not required IFOS Chloroacetaldehyde Acrolein Causes encephalopathy Causes hemorrhagic cystitis IPM-tris (molecule) Therapeutic metabolite (Palifosfamide-tris)

  3. DNA cross linking by Palifosfamide 5 ' - X - G - X - C - X - 3 ' 5 ' - X - G - C - X - X - 3 ' 5 ' - X - G - X - X - C - 3 ' 3 ' - X - C - X - X - G - 5 ' 3 ' - X - C - G - X - X - 5 ' (G-C sequence) (G-X-X-C sequence) C H 2 Palifosfamide (7 atom crosslink) (G-X-C sequence) C H 2 N H P - O H O H N - C - C H H 2 2 3' - X - C - X - G - X - 5' The 7-atom crosslink from palifosfamide prevents DNA repair Dong et al. Proc. Natl. Acad. Sci. USA 92: 12170-12174, 1995 Struck et al. Cancer Chemother. Parmacol. 45: 59-62. 2000

  4. Preclinical Broad activity in tumor cell lines and human xenografts including osteosarcomas and soft tissue sarcomas Active in ifosfamide- and cyclophosphamide- resistant cell lines and xenografts platinum–resistant p388 leukemia/ lymphoma murine model Orally active in p388 leukemia/ lymphoma model and in MX-1 breast cancer xenografts

  5. Synergy with DoxorubicinXenograft OS31 Palifosfamide (ZIO-201, IPM-tris) + Doxorubicin: tumor size Palifosfamide + Doxorubicin: Survival 100 80 60 Tumor volume, mm3 Survival probability (%) 40 20 days 0 20 30 40 50 60 70 80 90 days

  6. Clinical Activity Phase I - expected safety profile (ASCO 2006) MTD (Lysine) ~ 400 mg/m2 iv Days 1,2,3 Phase II single agent, advanced sarcoma (CTOS 2007) Best response: partial response Phase I palifosfamide/doxorubicin (ASCO 2009) MTD (Tris-mannitol) 150 mg/m2 iv Days 1,2,3 / 75 mg/m2 iv Day 1 2/8 sarcoma responders

  7. Study Design • Randomized, multicenter, multinational study in patients diagnosed with unresectable / metastatic soft-tissue sarcoma Arm A: Palifosfamide 150 mg/m2 Days 1,2,3 Doxorubicin 75 mg/m2 Day 1 Continuation with Palifosfamide 150 mg/m2 Days 1,2,3 Stratifiedrandomization Arm B: Doxorubicin 75 mg/m2 Day 1 • Treatment is repeated every 3 weeks x 6 cycles • Response evaluations every 6 weeks until progression

  8. Study Design Stratification by • Age: >65 or <65 years • Histologic subtype: • Leiomyosarcoma • Synovial sarcoma • Others

  9. Endpoints Primary Progression Free Survival (PFS) Secondary Response (RECIST version 1.0) Survival Safety

  10. Statistical Considerations Trial was powered to show the observed HR for PFS significance would be 0.75  An independent DSMB was convened at predetermined points to review data: Safety analyses took place following completion of the first cycle of therapy for the 20th subject A formal interim PFS efficacy analysis to determine whether to continue, amend, or terminate the study took place subsequent to enrollment of  >50% of patients, which coincided with the CTOS presentation  The pre-specified analysis for PFS in this presentation was for FDA EOP2 meeting.  

  11. Major Eligibility Criteria Documentation of sarcoma (excluding alveolar soft-part sarcoma, chondrosarcoma, DFSP, Ewing’s, GIST, Kaposi, mixed mesodermal tumor, osteosarcoma, radiation induced sarcomas, and unresectable low grade liposarcoma) Measurable disease per RECIST Front line or second line Prior treatment with ifosfamide acceptable Doxorubicin naïve Adequate bone marrow, liver, and renal functions

  12. Patients

  13. Baseline Characteristics of Treated Patients Age and Line of Therapy

  14. Baseline Characteristics of Treated Patients Histologic Sub-types Leiomyosarcoma Synovial Sarcoma Other 5 Liposarcoma 5 Myxofibrosarcoma (MFH) 3 MPNST 2 Spindle Cell Sarcoma 9 Liposarcoma 5 Myxofibrosarcoma (MFH) 2 MPNST 3 Spindle Cell Sarcoma

  15. Efficacy 62 eligible patients evaluated for PFS with 28 confirmed PFS events doxorubicin = 18 events palifosfamide + doxorubicin = 10 events

  16. Primary Endpoint - PFS Hazard ratio = 0.427 (95% CI: 0.191, 0.951) favoring palifosfamide + doxorubicin (p-value = 0.019) Median PFS: Doxorubicin = 4.4 months Palifosfamide + Doxorubicin = 7.8 months

  17. 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 1 2 3 4 5 6 MONTHS PFS: Patients Receiving/Censored at ≤ 6 Cycles (omitting effect of ongoing or cross-over palifosfamide) palifosfamide + doxorubicin (30) doxorubicin (32) p = 0.023 HR = 0.396

  18. Confirmed Response Rate

  19. Safety

  20. Safety Comparison No encephalopathy No hemorrhagic cystitis No mesna No renal Fanconi syndrome Similar bone marrow suppression

  21. Summary PFS: Hazard ratio is 0.427 (95% CI: 0.191-0.951) favoring palifosfamide + doxorubicin (p-value = 0.019) Median improvement 3.4 months (4.4 vs 7.8 months) Response Rate: 23% vs 9% Safety: Clinically similar between arms

  22. Conclusions Palifosfamide in combination with doxorubicin is Well-tolerated Given in the outpatient setting Active in soft tissue sarcoma A randomized phase III study, with similar design, is in very late stage of planning

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