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 CenterSanta Monica, California

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Targeting Tumors Using Endogenous Albumin

Acid-sensitive linker coupled to doxorubicinbinds 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.

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Aldoxorubicin First-line STS Phase 2b Trial Design

ScreenedN=140

2:1 Randomization N=123

Aldoxorubicin350mg/m2

(260mg/m2 dox equiv.)Every 3wk up to 6 cycles

N=83

Doxorubicin75mg/m2

Every 3wk up to 6 cyclesN=40

3 subjects randomized but not

dosed

14 screen failures

CT Scans every 6 weeks

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Patient Characteristics

Characteristics Aldoxorubicin DoxorubicinN 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 2.5

ECOG, n (%)

0-1 96 92

2 4 8

Completed Cycles, median (range) 6 (1-6) 4 (1-6)

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Disease Characteristics

Presented by: Sant Chawla, M.D.

Histopathology (as determined by investigator)

AldoxorubicinN = 83

DoxorubicinN = 40

Leiomyosarcoma, (%) 34 35

Liposarcoma, (%) 16 15

Fibrosarcoma, (%) 14 10

Synovial sarcoma, (%) 6 10

Others, (%) 30 30

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Primary Endpoint: PFS

All SubjectsIntent-to-treat

P Value

Scans Read by Investigator

Aldoxorubicin 8.4 monthsP=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

Aldoxorubicin 5.7 monthsP=0.014

Doxorubicin 2.8 months

Improvement over dox 2.9 mos. (104%)

Hazard ratio 0.584 (0.37-0.93) P=0.024

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K-M Curve - Investigator Assessment

3.7 month improvementHR: 0.419, p=0.0007

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K-M Curve – Central Lab Assessment

2.9 month improvementHR: 0.584, p=0.024

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PFS at 6 Months Results

All SubjectsIntent-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%

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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%

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Waterfall Plot - Investigator

Aldoxorubicin

64.5% had tumor shrinkage

Doxorubicin

41.2% had tumor shrinkage

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Waterfall Plot – Blinded Central Lab

Aldoxorubicin

60.8% had tumor shrinkage

Doxorubicin

39.4% had tumor shrinkage

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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

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Comparison to Current STS Treatments

CytRx Phase 2b

Investigator assessed

EORTC Phase 3

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%

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Comparison to TH-302 + Doxorubicin

CytRx Phase 2b

Investigator assessed

Phase 2TH-302 + DoxorubicinInvestigator assessed

Aldoxorubicin (max. 6 doses) TH-302 + Doxorubicin

N 83 91

Median PFS (months) 8.4 6.5

PFS-6 months 68% 58%

ORR 21.7% 36% (30% without maintenance)

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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 20

Nausea/vomiting 7.2 0

Mucositis 10.8 2.5

Fatigue/weakness 6.0 5.0

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Minimal Alopecia Even After 8 Cycles of Aldoxorubicin

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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

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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.

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Phase 3 Trial Design: 2nd-line STS

Soft tissue sarcoma patients that have relapsed or are refractory to prior chemotherapy

1:1 RandomizationN=400

Aldoxorubicin350mg/m2

(260mg/m2 dox equiv.)Every 3weeks until disease progression

N=200

Physicians Choice:Doxorubicin DacarbazineIfosfamide

Gemcitabine+docetaxelPazopanib

N=200

Primary Endpoint: PFS

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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.