Preliminary Efficacy and Safety of INNO-206 Compared to Doxorubicin in Advanced Soft Tissue Sarcoma

This is a phase 2b, randomized, open-label, prospective, multicenter study comparing treatment with INNO 206 to doxorubicin in subjects with metastatic, locally advanced, or unresectable soft tissue sarcomas who have not been previously treated with any chemotherapy except potentially as adjuvant or neoadjuvant chemotherapy, and no evidence of tumor recurrence has occurred for at least 12 months.

One hundred five subjects will be enrolled and randomized 2:1 to receive either INNO-206 or doxorubicin. INNO-206 at a dosage of 350 mg/m2 (doxorubicin equivalents of 260 mg/m2) will be administered as a 30 minute IVI on Day 1 of each cycle to approximately 70 subjects. Doxorubicin (75 mg/m2) will be administered to approximately 35 subjects on Day 1 of each cycle. An individual cycle of therapy will be defined as a 3-week (21-day) period. Cycles will be repeated every 3 weeks. Multiple cycles may be administered until the subject is withdrawn from therapy or until a maximum of 6 cycles are administered. Overall response rates as well as individual categories of response (CR, PR, SD, and PD) will be determined using RECIST 1.1.\[28\] Time-to-event endpoints, including PFS and OS will be assessed using the Kaplan Meier method.\[30\] Evaluation of 4- and 6-month progression-free survival will also be performed. Toxicity (adverse events) will be recorded using the NCI CTCAE, version 4.0 (published 28 May 2009).

Eligibility Criteria:
Inclusion Criteria:

* Age between 15-80 years (US only), and 18-80 (rest of world (ROW)), male or female.
* Adjuvant or neoadjuvant chemotherapy (including doxorubicin) allowed if no tumor recurrence for at least 12 months since the last measurement, beginning or end of last chemotherapy.
* Histologically or cytologically confirmed, locally advanced, unresectable, and/or metastatic soft tissue sarcoma of intermediate or high grade.
* Capable of providing informed consent and complying with trial procedures.
* ECOG performance status 0-2.
* Life expectancy \> 12 weeks.
* Measurable tumor lesions according to RECIST 1.1 criteria.
* Women must not be able to become pregnant (e.g. post-menopausal for at least 1 year, surgically sterile, or practicing adequate birth control methods) for the duration of the study. (Adequate contraception includes: oral contraception, implanted contraception, intrauterine device implanted for at least 3 months, or barrier method in conjunction with spermicide.)
* Women of child bearing potential must have a negative serum or urine pregnancy test at the Screening Visit and be non-lactating.
* Geographic accessibility to the site that ensures the subject will be able to keep all study-related appointments.

Exclusion Criteria:

* Prior chemotherapy unless for adjuvant or neoadjuvant therapy with no tumor recurrence for at least 12 months.
* Prior exposure to \> 3 cycles or 225 mg/m2 of doxorubicin or Doxil®.
* Palliative surgery and/or radiation treatment less than 4 weeks prior to Randomization.
* Exposure to any investigational agent within 30 days of Randomization.
* Current Stage 1 or 2 soft tissue sarcomas.
* Current evidence/diagnosis of alveolar soft part sarcoma, chondrosarcoma, rhabdomyosarcoma, osteosarcoma, gastrointestinal stromal tumor (GIST), dermatofibrosarcoma, Ewing's sarcoma, Kaposi's sarcoma, mixed mesodermal tumor, clear cell sarcomas and unresectable low grade liposarcomas.
* Central nervous system metastasis
* History of other malignancies except cured basal cell carcinoma, superficial bladder cancer or carcinoma in situ of the cervix unless documented free of cancer for \> 5 years.
* Laboratory values: Screening serum creatinine \> 1.5x upper limit of normal (ULN), alanine aminotransferase (ALT) \> 3 × ULN or \>5 × ULN if liver metastases are present, total bilirubin \> 3 × ULN, absolute neutrophil count \< 1,500/mm3, platelet concentration \< 100,000/mm3, hematocrit level \< 25% for females or \< 27% for males, or coagulation tests (prothrombin time \[PT\], partial thromboplastin time \[PTT\], International Normalized Ratio \[INR\]) \> 1.5 × ULN, albumin \< 2.0 g/dL.
* Clinically evident congestive heart failure \> class II of the New York Heart Association (NYHA) guidelines.
* Current, serious, clinically significant cardiac arrhythmias, defined as the existence of an absolute arrhythmia or ventricular arrhythmias classified as Lown III, IV or V.
* Baseline QTc \> 470 msec and/or previous history of QT prolongation while taking other medications. Concomitant use of medications associated with a high incidence of QT prolongation is not allowed.
* History or signs of active coronary artery disease with or without angina pectoris.
* Serious myocardial dysfunction defined as scintigraphically (e.g. MUGA, myocardial scintigram) or ultrasound determined absolute left ventricular ejection fraction (LVEF) \< 45% of predicted.
* History of HIV infection.
* Active, clinically significant serious infection requiring treatment with antibiotics, anti-virals or anti-fungals.
* Major surgery within 3 weeks prior to Randomization.
* Substance abuse or any condition that might interfere with the subject's participation in the study or in the evaluation of the study results.
* Any condition that is unstable and could jeopardize the subject's participation in the study.