0. 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

1. 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.

2. 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

3. 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)

4. 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.

5. 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 ( )
P=0.0007
Scans Read by Blinded Central Lab
5.7 months
P=0.014
2.8 months
2.9 mos. (104%)
0.584 ( )
P=0.024

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

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

8. 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%

9. 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%

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

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

12. 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

13. 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%

14. Comparison to TH-302 + Doxorubicin
CytRx Phase 2b
Investigator assessed
Phase 2
TH 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)

15. 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

16. Minimal Alopecia Even After 8 Cycles of Aldoxorubicin

17. 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

18. 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.

19. 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

20. 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.