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Background: Aldoxorubicin is a novel prodrug that covalently binds albumin in the circulation. Doxorubcin is cleaved in low pH environments, allowing administration of 3 1/2 to 4 fold higher doses than standard doxorubicin and 10-fold greater cumulative doses. Patients with metastatic or unresectable soft tissue sarcomas (STS) who have failed prior chemotherapies have a poor prognosis with progresson-free survival (PFS) of around 2-4.5 months and overall survival (OS) of 9-12 months. Several agents have been tested as palliative therapy with these patients including ifosfamide, gemcitabine/docetaxel, dacarbazine and pazopanib. Aldoxorubicin may improve upon the activity of these drugs. Trial design: Phase 3 Open label 400 subjects with intermediate or high grade locally advanced or metastatic STS randomized 1:1 to either aldoxorubicin (A) (350 mg/m2 iv Day 1 every 3 weeks) or investigator's choice (IC) as comparator of any of these treatments: (i) dacarbazine (1000 mg/m2 iv Day 1 every 3 weeks); (ii) pazopanib 800 mg po (iii) gemcitbine (900 mg/m2 iv Days 1 & 8) plus docetaxel (100 mg/m2 iv Day 8) every 3 weeks; (iv) doxorubicin (75 mg/m2 iv Day 1 every 3 weeks); (v) ifosfamide (2 gm/m2 iv Days 1-4 every 3 weeks). The investigative site prespecifies 3 treatment regimens for which CytRx will supply the drugs. Treat to progression or unacceptable toxicity Major inclusions: histological confirmation of tumor type with tissue provided for central review; relapsed/refractory after >/= 1 course of chemotherapy; measurable tumor by RECIST 1.1; ECOG 0-2 Major exclusions:prior exposure to> 375 mg/m2 doxorubicin; inadequate tumor specimen; diagnosis of GIST, alveolar soft part, rhabdo, Ewing's, Kaposi's, osteo, extraskeletal myxoid chondro, dermatofbro, or clear cell sarcomas, or mixed mesodermal tumor; clinically significant cardiac disease, LFTs> 3x (no mets) or 5x (liver mets) normal; ANC Disclosure: S. Wieland: CytRx Employee, Salary and Stock options; D. Levitt: CytRx Employee; Salary and Stock Options. All other authors have declared no conflicts of interest.

Background We have studied the safety and tumor response of a doxorubicin conjugate, INNO-206, in patients with metastatic STS who progressed on prior chemotherapy. INNO-206 is a conjugate of doxorubicin attached to an acid-sensitive linker that binds covalently to cysteine-34 in circulating albumin. Methods INNO-206 was administered IV at 350 mg/m2 (260 mg/m2 dox. eq.) every 21 days for up to 8 consecutive cycles. Tumor response was monitored every other month and treatment continued until tumor progression or unacceptable toxicity. Standard safety monitoring was performed and cardiac function was followed periodically using MUGA or cardiac ultrasound. Results As of May 1, 2012, 19 patients were entered in the study. 13/19 patients had STS of various types. Of the initial 19 patients treated at the 350 mg/m2 dose, no individuals experienced a grade 3 or 4 non-hematological toxicity during Cycle 1. The majority of patients demonstrated transient grade 3 or 4 neutropenias that resolved prior to the next cycle with and without G-CSF treatment. No patient exhibited relevant cardiotoxicity as determined by MUGA or cardiac ultrasound. Of 19 patients, serious adverse events included febrile neutropenia (3) sepsis (1) and mucositis (1). Of the 13 patients with STS, 5 objective partial responses (3 of whom received prior doxorubicin) are ongoing as well as 7 patients with stable disease (median 6.43 months, range 1-10.7+ months). 1/13 patients had progressive disease at the first evaluation. 2/19 patients died with the first cycle (1 PD, 1 sepsis). Conclusion INNO-206 is an active drug for the treatment of patients with advanced STS who have failed prior chemotherapy. Cumulative doses of 2000 mg/m2 of doxorubicin equivalents have been achieved, which is over 3½ x the peak cumulative dose of standard doxorubicin. Adverse events are primarily hematological and no cardiotoxicity has been observed. Disclosure S. Chawla: Corporate sponsored research from CytRx Corporation. S. Wieland: Salary and stock ownership from CytRx Corporation. D. Levitt: Salaryand stockownership from CytRx Corporation. All other authors have declared no conflicts of interest.