Randomized phase 2b trial comparing first-line treatment with aldoxorubicin versus doxorubicin in patients with advanced soft tissue sarcomas Sant Chawla, M.D. Principal Investigator Director, Sarcoma Oncology Center Santa Monica, California

Targeting Tumors Using Endogenous Albumin Acid-sensitive linker coupled to doxorubicin binds covalently to circulating albumin in < 5 minutes Drug Linker Predetermined Breaking point Albumin After infusion, linker forms covalent bond to cysteine-34 on albumin Able to deliver several times more drug because drug is inactive until released at the tumor Linker can be used with many types of cancer drugs: anthracyclines, taxanes, camptothecins, platinums, etc.

Aldoxorubicin First-line STS Phase 2b Trial Design Screened N=140 14 screen failures 2:1 Randomization N=123 3 subjects randomized but not dosed Aldoxorubicin 350mg/m2 (260mg/m2 dox equiv.) Every 3wk up to 6 cycles N=83 Doxorubicin 75mg/m2 Every 3wk up to 6 cycles N=40 CT Scans every 6 weeks

Patient Characteristics Aldoxorubicin Doxorubicin N 83 40 Age, median (range) 54.0 (21-77) 54.0 (23-77) Male / Female, n (%) 46 / 54 45 / 55 Race, n (%) Caucasian 74 80 Black or African American 1 2.5 Asian 19 15 Other 6 ECOG, n (%) 0-1 96 92 2 4 8 Completed Cycles, median (range) 6 (1-6) 4 (1-6)

Disease Characteristics Histopathology (as determined by investigator) Aldoxorubicin N = 83 Doxorubicin N = 40 Leiomyosarcoma, (%) 34 35 Liposarcoma, (%) 16 15 Fibrosarcoma, (%) 14 10 Synovial sarcoma, (%) 6 Others, (%) 30 Presented by: Sant Chawla, M.D.

Primary Endpoint: PFS All Subjects Intent-to-treat P Value Scans Read by Investigator Aldoxorubicin 8.4 months P=0.0004 Doxorubicin 4.7 months Improvement over dox 3.7 mos. (79%) Hazard ratio 0.419 (0.25-0.69) P=0.0007 Scans Read by Blinded Central Lab 5.7 months P=0.014 2.8 months 2.9 mos. (104%) 0.584 (0.37-0.93) P=0.024

K-M Curve - Investigator Assessment 3.7 month improvement HR: 0.419, p=0.0007

K-M Curve – Central Lab Assessment 2.9 month improvement HR: 0.584, p=0.024

PFS at 6 Months Results All Subjects Intent-to-Treat P Value Scans Read by Investigator Aldoxorubicin 68.1% P=0.002 Doxorubicin 36.6% Improvement over dox 86.1% Scans Read by Blinded Central Lab 45.7% P=0.02 22.9% 99.6%

Overall Response Rate Results Aldoxorubicin Doxorubicin Scans Read by Investigator Complete Response 2.4% 0% Partial Response 19.3% 5.0% Overall Response Rate 21.7% Scans Read by Central Lab 23.8%

Waterfall Plot - Investigator Aldoxorubicin 64.5% had tumor shrinkage Doxorubicin 41.2% had tumor shrinkage

Waterfall Plot – Blinded Central Lab Aldoxorubicin 60.8% had tumor shrinkage Doxorubicin 39.4% had tumor shrinkage

Overall Survival - Preliminary Too early to determine OS due to prolonged survival of patients in study. As of September 15, 2014: Higher % deaths and lower % still being followed in doxorubicin-treated subjects. Lower % deaths and higher % still being followed in aldoxorubicin-treated subjects. % Deaths % Lost to F/U % Still Followed Aldoxorubicin 42 19 39 Doxorubicin 55 18 27

Comparison to Current STS Treatments CytRx Phase 2b Investigator assessed EORTC Phase 3 Dox vs. dox+ ifosfamide Aldox Dox Dox+ ifos N 83 40 215 217 Age 54 (21-77) 54 (23-77) 48 (18-60) 47 (18-63) PFS (months) 8.4 4.7 7.4 4.6 P value 0.0004 0.003 OS (months) NA 14.3 12.8 0.076 ORR 21.7% 5.0% 26.5% 13.6%

Comparison to TH-302 + Doxorubicin CytRx Phase 2b Investigator assessed Phase 2 TH-302 + Doxorubicin Aldoxorubicin (max. 6 doses) N 83 91 Median PFS (months) 8.4 6.5 PFS-6 months 68% 58% ORR 21.7% 36% (30% without maintenance)

Grade 3/4 TEAEs Aldoxorubicin Doxorubicin N=83 N=40 Event (%) Neutropenia 40 20 Neutropenic fever 15.7 17.5 Thrombocytopenia 6 5 Anemia 13.2 Nausea/vomiting 7.2 Mucositis 10.8 2.5 Fatigue/weakness 6.0 5.0

Minimal Alopecia Even After 8 Cycles of Aldoxorubicin

Cardiac Evaluation Aldoxorubicin Doxorubicin Median Cumulative Dose (mg/m2) [range] 2,100* [350-2,800] 300* [75-450] % subjects with ≥15% decrease in LVEF 8% 34% % subjects with ≥15% increase in LVEF 15% 3% % subjects with ≤45% of expected value 0% 5.7% *Maximum of 6 cycles allowed per protocol

Conclusions Aldoxorubicin significantly increases PFS, PFS at 6 months and ORR compared to doxorubicin therapy for first line STS. Grade 3 or 4 neutropenia, mucositis and nausea/vomiting are higher in aldoxorubicin-treated patients but are not treatment limiting. The aldoxorubicin patients received more than 5 times the cumulative amount of doxorubicin in this study than the doxorubicin patients without any evidence of clinically relevant decreased LVEF, and in more instances an increase in LVEF, either by MUGA or echocardiogram. A phase 3 pivotal trial under a SPA is ongoing for relapsed/refractory STS. Presented by: Sant Chawla, M.D.

Phase 3 Trial Design: 2nd-line STS Soft tissue sarcoma patients that have relapsed or are refractory to prior chemotherapy 1:1 Randomization N=400 Aldoxorubicin 350mg/m2 (260mg/m2 dox equiv.) Every 3weeks until disease progression N=200 Physicians Choice: Doxorubicin Dacarbazine Ifosfamide Gemcitabine+docetaxel Pazopanib N=200 Primary Endpoint: PFS

Aldoxorubicin + Ifosfamide Study A Single Center, Open-Label Phase 1b/2 Study to Investigate the Preliminary Safety and Activity of Aldoxorubicin plus Ifosfamide/Mesna in Subjects with Metastatic, Locally Advanced, or Unresectable Soft Tissue Sarcoma Aldoxorubicin administered at either 170, 250 or 350 mg/m2 (125, 185 and 260 mg/m2 doxorubicin equivalents) intravenously on Day 1 every 28 days plus 1 gm/m2 ifosfamide by continuous intravenous infusion for 14 days via a portable/ambulatory infusion pump every 28 days until disease progression, unacceptable toxicity or withdrawal of consent. Tumor response will be monitored every 8 weeks from Cycle 1-Day 1 through week 33, and then every 12 weeks until disease progression using the RECIST 1.1 criteria.