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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;
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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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
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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
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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
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Synergy with Doxorubicin Xenograft OS31
0
1000
2000
3000
4000
5000
6000
7000
10 20 30 40 50 60
Vehicle IPM-tris, 12 mg/kg Dox, 8 mg/kg Combination
Palifosfamide (ZIO-201, IPM-tris) + Doxorubicin: tumor size
Tum
or
volu
me,
mm
3
days
Palifosfamide + Doxorubicin: Survival
20 30 40 50 60 70 80 90
100
80
60
40
20
0
Su
rviv
al p
rob
ab
ility
(%
)
days
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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
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Study Design• Randomized, multicenter, multinational study in
patients diagnosed with unresectable / metastatic soft-tissue sarcoma
Arm B:
Doxorubicin 75 mg/m2 Day 1
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
Str
atif
ied
ra
nd
om
izat
ion
• Treatment is repeated every 3 weeks x 6 cycles
• Response evaluations every 6 weeks until progression
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Study Design
Stratification by
– Age: >65 or <65 years
– Histologic subtype:• Leiomyosarcoma• Synovial sarcoma• Others
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Endpoints
• Primary–Progression Free Survival (PFS)
• Secondary–Response (RECIST version 1.0)–Survival–Safety
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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.
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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
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Patients
N Palifosfamide+Doxorubicin
Doxorubicin
Enrolled 67 34 33
Treated 66 33 33
Eligible 62 30 32
Ongoing single agent palifosfamide
16 7 9
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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
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Palifosfamide and Doxorubicin
9
2
22
Baseline Characteristics of Treated Patients Histologic Sub-types
Doxorubicin
112
20
5 Liposarcoma5 Myxofibrosarcoma (MFH)3 MPNST2 Spindle Cell Sarcoma
9 Liposarcoma5 Myxofibrosarcoma (MFH)2 MPNST3 Spindle Cell Sarcoma
Leiomyosarcoma Synovial Sarcoma Other
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Efficacy
62 eligible patients evaluated for PFS with
•28 confirmed PFS events
- doxorubicin = 18 events
- palifosfamide + doxorubicin = 10 events
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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
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0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1 2 3 4 5 6MONTHS
p = 0.023HR = 0.396
palifosfamide + doxorubicin (30)
doxorubicin (32)
PFS: Patients Receiving/Censored at ≤ 6 Cycles (omitting effect of ongoing or cross-over palifosfamide)
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Confirmed Response Rate
Palifosfamide+DoxorubicinDoxorubici
n
N=30 N=32
Partial Responders 7 (23%) 3 (9%)
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SafetyPalifosfamide +
Doxorubicin (N=33)
Doxorubicin(N=33)
Grade 3+ Events >10% N % N %
Neutropenia 13 40 12 36
Thrombocytopenia 4 12 0 0
SAEs >5%
Elevated creatinine 3 9 1 3
Febrile neutropenia 1 3 2 6 Dose reductions 8 24 9 27
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Safety Comparison
• No encephalopathy• No hemorrhagic cystitis• No mesna• No renal Fanconi syndrome • Similar bone marrow suppression
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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
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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