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

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

model and in MX-1 breast cancer xenografts

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

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

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

Study Design

Stratification by

– Age: >65 or <65 years

– Histologic subtype:• Leiomyosarcoma• Synovial sarcoma• Others

Endpoints

• Primary–Progression Free Survival (PFS)

• Secondary–Response (RECIST version 1.0)–Survival–Safety

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.  

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

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

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

Efficacy

62 eligible patients evaluated for PFS with

•28 confirmed PFS events

- doxorubicin = 18 events

- palifosfamide + doxorubicin = 10 events

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

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)

Confirmed Response Rate

Palifosfamide+DoxorubicinDoxorubici

n

N=30 N=32

Partial Responders 7 (23%) 3 (9%)

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

Safety Comparison

• No encephalopathy• No hemorrhagic cystitis• No mesna• No renal Fanconi syndrome • Similar bone marrow suppression

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

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