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
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A Phase II Randomized Controlled Trial of Palifosfamide Plus Doxorubicin vs. Doxorubicin In Patients with Soft Tissue Sarcoma (PICASSO) C. F. Verschraegen,
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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;
Memorial Sloan-Kettering Cancer Center, New York, NY
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
Chloroacetaldehyde
Acrolein
IFOS
IPM-tris (molecule) Therapeutic metabolite
(Palifosfamide-tris)
Causes hemorrhagic
cystitis
Causes encephalopathy
DNA cross linking by Palifosfamide
Palifosfamide(7 atom crosslink)(G-X-C sequence)
CH2
NH
P-OHOHN-CH2-CH2
5' - X - G - X - C - X - 3'
CH2
3' - X - C - X - G - X - 5'
5' - X - G - C - X - X - 3' 5' - X - G - X - X - C - 3'3' - X - C - G - X - X - 5' 3' - X - C - X - X - G - 5'
(G-C sequence) (G-X-X-C sequence)
Dong et al. Proc. Natl. Acad. Sci. USA 92: 12170-12174, 1995Struck et al. Cancer Chemother. Parmacol. 45: 59-62. 2000
The 7-atom crosslink from palifosfamide prevents DNA repair
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
• Measurable disease per RECIST • Front line or second line • Prior treatment with ifosfamide acceptable• Doxorubicin naïve • Adequate bone marrow, liver, and renal
functions
Patients
N Palifosfamide+Doxorubicin
Doxorubicin
Enrolled 67 34 33
Treated 66 33 33
Eligible 62 30 32
Ongoing single agent palifosfamide
16 7 9
Baseline Characteristics of Treated Patients Age and Line of Therapy
Age NPalifosfamide+Doxorub
icinDoxorubici
n
>65 23 12 11
<65 43 21 22Median age 66 57 years
(19-83 years)57 years
(29-80 years)Line of Therapy
Front-line 46 23 23
Second-line 20 10 10
Palifosfamide and Doxorubicin
9
2
22
Baseline Characteristics of Treated Patients Histologic Sub-types