A Phase II Multicenter, Parallel Group, Randomized Study of Palifosfamide Tris Plus Doxorubicin Versus Doxorubicin in Subjects With Unresectable or Metastatic Soft-tissue Sarcoma

Inclusion Criteria:

1. Age ≥18 years

2. Histological or cytological documentation of sarcoma (excluding alveolar
soft-part sarcoma, chondrosarcoma, dermatofibrosarcoma, Ewing sarcoma, GIST, Kaposi
sarcoma, mixed mesodermal tumor, osteosarcoma, radiation induced sarcomas, and
unresectable low grade liposarcoma) who have failed ≤2 prior regimens including
adjuvant therapy, or ≤1 prior regimen for metastatic/unresectable disease, and for
whom treatment with doxorubicin is considered medically acceptable. Prior treatment
with IFOS is acceptable.

3. Have measurable disease as per RECIST criteria (Appendix 2)

4. ECOG Performance Status of 0 or 1 (Appendix 3)

5. Anthracyclin naïve

6. Life expectancy of ≥12 weeks

7. Adequate bone marrow, liver, and renal function, as assessed by the following
laboratory requirements conducted within 14 days prior to dosing:

1. Hemoglobin ≥9.0 g/dL

2. Absolute neutrophil count (ANC) ≥1,500/mm3

3. Platelet count 100,000/mm3

4. Total bilirubin ≤1.5×ULN (upper limit of normal)

5. ALT and AST ≤2.5×ULN or 5×ULN with hepatic disease

6. Partial thromboplastin [PT]-INR/activated partial thromboplastin time [PTT]
<1.5×ULN (≤2.0×ULN for subjects on anticoagulation prophylactic regimen).
Subjects who are being therapeutically anticoagulated with an agent such as
Coumadin (warfarin sodium) or heparin are allowed provided there is no prior
evidence of underlying abnormality in coagulation parameters. If an interaction
between study drug and anticoagulant is suspected, anticoagulation monitoring
should be increased as appropriate.

7. Serum creatinine ≤ULN

8. Written informed consent must be obtained from a potential subject prior to the
conduct of any study-specific procedures

9. Male and female subjects must agree to use adequate birth control measures/barrier
control during the course of the trial

10. Women of childbearing potential must have a urine pregnancy test performed within 14
days of the start of treatment

Exclusion Criteria:

1. Has any one of the following sarcoma sub types: alveolar soft-part sarcoma,
chondrosarcoma, dermatofibrosarcoma, Ewing sarcoma, GIST, Kaposi sarcoma, mixed
mesodermal tumor, osteosarcoma, radiation induced sarcomas, and unresectable low
grade liposarcoma.

2. Clinically evident congestive heart failure >Class II of the New York Heart
Association (NYHA) guidelines (Appendix 4)

3. Serious, clinically significant cardiac arrhythmias, defined as the existence of an
absolute arrhythmia, or ventricular arrhythmias classified as Lown III, IV, or V
(Appendix 4)

4. History and/or signs of active coronary artery disease/ischemia with or without
angina pectoris

5. Serious myocardial dysfunction defined as scintigraphically (MUGA [multiple gated
acquisition scan], myocardial scintigram) or ultrasound-determined absolute left
ventricular ejection fraction (LVEF) <45%

6. History of HIV infection

7. Prior nephrectomy or history of urinary tract obstruction

8. Active, clinically serious infection requiring systemic antibacterial, antifungal, or
antiviral therapy

9. Any major surgery within 3 weeks prior to start of treatment

10. Metastatic brain or meningeal tumors, unless the subject is >6 months from definitive
therapy and has a negative imaging study within 4 weeks of study entry. In addition,
the subject must not be undergoing acute steroid therapy or taper (chronic steroid
therapy is acceptable, provided the dose is stable for 1 month prior to study start,
and following screening radiographic studies).

11. Previous malignancy (except cervical carcinoma in situ, adequately treated basal cell
carcinoma, or superficial bladder tumors [Ta, Tis, & T1] or other malignancies
curatively treated >5 years prior to entry)

12. Pregnancy or lactation

13. Substance abuse or medical, psychological, or social conditions that may interfere
with the subject's participation in the study or evaluation of the study results

14. Any condition that is unstable or could jeopardize the safety of a subject and
his/her compliance with the protocol requirements

In addition, use of the following therapies and medications—prior or
concomitant—would exclude a subject from this study:

15. Anticancer chemotherapy, immunotherapy, or any investigational drug therapy during
the study or within 4 weeks of study entry (6 weeks for Mitomycin C)

16. Prior treatment with doxorubicin

17. Radiotherapy within 4 weeks of study entry (palliative radiation to bone lesions is
permitted if started or planned prior to Cycle 1, Day 1)

18. Bone marrow transplant or stem cell rescue within 4 months of study entry

19. Growth factors such as G-CSF (granulocyte colony-stimulating factor/filgrastim), or
biological response modifiers within 3 weeks of study entry