Aldoxorubicin vs. Doxorubicin in Soft Tissue Sarcomas: Phase 2b Trial Results

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 Albumin After infusion, linker forms covalent bond to cysteine-34 on albumin Predetermined Breaking point 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. 1

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 2

Patient Characteristics Characteristics N Aldoxorubicin 83 Doxorubicin 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 2.5 ECOG, n (%) 0-1 96 92 2 4 8 Completed Cycles, median (range) 6 (1-6) 4 (1-6) 3

Disease Characteristics Aldoxorubicin N = 83 Doxorubicin N = 40 Histopathology (as determined by investigator) Leiomyosarcoma, (%) 34 35 Liposarcoma, (%) 16 15 Fibrosarcoma, (%) 14 10 Synovial sarcoma, (%) 6 10 Others, (%) 30 30 Presented by: Sant Chawla, M.D. 4

Primary Endpoint: PFS All Subjects Intent-to-treat P Value Scans Read by Investigator Aldoxorubicin 8.4 months P=0.0004 Doxorubicin Improvement over dox Hazard ratio 4.7 months 3.7 mos. (79%) 0.419 (0.25-0.69) P=0.0007 Scans Read by Blinded Central Lab Aldoxorubicin Doxorubicin Improvement over dox Hazard ratio 5.7 months 2.8 months 2.9 mos. (104%) 0.584 (0.37-0.93) P=0.014 P=0.024 5

K-M Curve - Investigator Assessment 3.7 month improvement HR: 0.419, p=0.0007 6

K-M Curve Central Lab Assessment 2.9 month improvement HR: 0.584, p=0.024 7

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 Aldoxorubicin 45.7% P=0.02 Doxorubicin 22.9% Improvement over dox 99.6% 8

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% 5.0% Scans Read by Central Lab Complete Response 0% 0% Partial Response 23.8% 0% Overall Response Rate 23.8% 0% 9

Waterfall Plot - Investigator Aldoxorubicin 64.5% had tumor shrinkage Doxorubicin 41.2% had tumor shrinkage 10

Waterfall Plot Blinded Central Lab Aldoxorubicin 60.8% had tumor shrinkage Doxorubicin 39.4% had tumor shrinkage 11

Overall Survival - Preliminary Too early to determine OS due to prolonged survival of patients in study. As of September 15, 2014: % Lost to F/U 19 18 % Still Followed 39 27 % Deaths Aldoxorubicin Doxorubicin 42 55 Higher % deaths and lower % still being followed in doxorubicin- treated subjects. Lower % deaths and higher % still being followed in aldoxorubicin-treated subjects. 12

Comparison to Current STS Treatments CytRx Phase 2b EORTC Phase 3 Investigator assessed Dox vs. dox+ ifosfamide Aldox Dox Dox+ ifos Dox 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 NA 14.3 12.8 P value 0.076 ORR 21.7% 5.0% 26.5% 13.6% 13

Comparison to TH-302 + Doxorubicin CytRx Phase 2b Phase 2 TH-302 + Doxorubicin Investigator assessed Investigator assessed Aldoxorubicin (max. 6 doses) TH-302 + Doxorubicin N 83 91 Median PFS (months) 8.4 6.5 PFS-6 months 68% 58% 36% (30% without maintenance) ORR 21.7% 14

Grade 3/4 TEAEs Aldoxorubicin N=83 (%) Doxorubicin N=40 (%) Event Neutropenia 40 20 Neutropenic fever 15.7 17.5 Thrombocytopenia 6 5 Anemia 13.2 20 Nausea/vomiting 7.2 0 Mucositis 10.8 2.5 Fatigue/weakness 6.0 5.0 15

Minimal Alopecia Even After 8 Cycles of Aldoxorubicin 16

Cardiac Evaluation Aldoxorubicin 2,100* [350-2,800] Doxorubicin 300* [75-450] Median Cumulative Dose (mg/m2) [range] % subjects with 15% decrease in LVEF % subjects with 15% increase in LVEF 8% 34% 15% 3% % subjects with 45% of expected value 0% 5.7% *Maximum of 6 cycles allowed per protocol 17

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. 18

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 Physicians Choice: Doxorubicin Dacarbazine Ifosfamide Gemcitabine+docetaxel Pazopanib N=200 Aldoxorubicin 350mg/m2 (260mg/m2 dox equiv.) Every 3weeks until disease progression N=200 Primary Endpoint: PFS 19

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. 20