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DRUG CONJUGATES BIND
COVALENTLY TO ALBUMIN: A NEW
APPROACH
Sant Chawla, M.D.
Director, Sarcoma Oncology Center
Santa Monica, California
Financial Disclosures
 Advisor, Research Support, and Travel Grant
 CytRx
 Threshold Pharmaceuticals
 GlaxoSmithKline
 Amgen
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The Importance of Albumin




Most abundant protein in human blood plasma
Transports hormones, fatty acids, metal ions, drugs
Buffers pH; T ½ = 20 days
Advanced cancers are nitrogen and nucleotide “hungry“
 Can lead to protein catabolism  ALBUMIN IS THE MAJOR SOURCE OF
ESSENTIAL AMINO ACIDS FOR CANCER CELLS
 Utilize the Enhanced Permeability and Retention effect for
macromolecules
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Enhanced Permeation and Retention
effect (EPR)
Physiological property of solid tumors
lymphatic capillary
Healthy
tissue
normaltissue
50 -300 nm
molecules
allSmall
Blood
stream
bloodstream
molecules
tumor tissue
macromolecules
Y. Matsumura, H. Maeda, Cancer Res. 46, 6387, 1986.
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Factors Affecting the EPR Effect of
Macromolecular Drugs in Solid Tumors
 Active angiogenesis and high vascular density
 Extensive production of vascular mediators that facilitate
extravasation, including
 Bradykinin, nitric oxide, VPF/VEGF, prostaglandins, matrix
metalloproteinases
 Defective vascular architecture:
 Lack of smooth muscle layer cells, lack of or reduced receptors for
angiotensin II, large gap in endothelial cell–cell junctions, anomalous
conformation (branching or stretching etc.).
 Impaired lymphatic clearance of macromolecules and
lipids from interstitial tissue causes retention
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Tumor relevant albumin-binding
proteins gp60 and SPARC
Schnitzer JE, Oh P. Antibodies to SPARC inhibit albumin binding to SPARC,
gp60, and microvascular endothelium, Am J Physiol. 1992 263:1872-9
Vessel lumen
Albumin
gp60
receptor
Endothelial cell
Tumor interstitium
SPARC
Tumor cells
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Targeting Tumors Using Endogenous
Albumin
Acid-sensitive linker coupled to doxorubicin
binds covalently to circulating albumin in < 5 minutes
Drug
Linker
Albumin
Predetermined
Breaking point


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.
Presented by: Sant Chawla, M.D.
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Mechanism of Aldoxorubicin
Dox
Linker
Albumin
2
Linker forms a covalent
bond within minutes to
the cysteine-34 of
serum albumin
1
Dox
3
Linker
Drug / linker conjugate
is infused into the patient
Aldoxorubicin
allows for 3.5x
the standard dose
of doxorubicin at
each cycle
Tumor cells
4
Albumin transports
drug to the tumor and
is taken up by the
tumor
Linker dissolves in the acidic (low pH) environment,
releasing the drug payload
7
Linker-dye conjugate binds to albumin and
preferentially collects in the tumor
Free dye,
no linker
Albumin bound dye
24 hour post IV infusion in SC colon tumor (LS174T)
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Aldoxorubicin First-line STS Phase 2b
Trial Design
Screened
N=140
14 screen failures
2:1 Randomization
N=123
Aldoxorubicin
350mg/m2
(260mg/m2 dox equiv.)
Every 3wk up to 6 cycles
N=83
3 subjects
randomized but not
dosed
Doxorubicin
75mg/m2
Every 3wk up to 6 cycles
N=40
CT Scans every 6 weeks
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Patient Characteristics
Characteristics
Aldoxorubicin
Doxorubicin
83
40
Age, median (range)
54.0 (21-77)
54.0 (23-77)
Male / Female, n (%)
46 / 54
45 / 55
74
80
1
2.5
Asian
19
15
Other
6
2.5
96
92
4
8
6 (1-6)
4 (1-6)
N
Race, n (%)
Caucasian
Black or African American
ECOG, n (%)
0-1
2
Completed Cycles, median (range)
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Disease Characteristics
Histopathology
Aldoxorubicin
N = 83
Doxorubicin
N = 40
Leiomyosarcoma, (%)
34
35
Liposarcoma, (%)
16
15
Fibrosarcoma, (%)
14
10
6
10
30
30
(as determined by investigator)
Synovial sarcoma, (%)
Others, (%)
Presented by: Sant Chawla, M.D.
11
PFS Results
All Subjects
Intent-to-treat
P Value
Scans Read by Investigator
Aldoxorubicin
8.4 months
Doxorubicin
4.7 months
Improvement over dox
Hazard ratio
P=0.0004
3.7 mos. (79%)
0.419 (0.25-0.69)
P=0.0007
Scans Read by Central Lab
Aldoxorubicin
5.7 months
Doxorubicin
2.8 months
Improvement over dox
Hazard ratio
P=0.014
2.9 mos. (104%)
0.584 (0.37-0.93)
P=0.024
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K-M Curve - Investigator Assessment
3.7 month improvement
HR: 0.419, p=0.0007
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K-M Curve – Central Lab Assessment
2.9 month improvement
HR: 0.584, p=0.024
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PFS at 6 Months Results
All Subjects
Intent-to-Treat
P Value
Scans Read by Investigator
Aldoxorubicin
68.1%
Doxorubicin
36.6%
Improvement over dox
P=0.002
86.1%
Scans Read by Central Lab
Aldoxorubicin
45.7%
Doxorubicin
22.9%
Improvement over dox
P=0.02
99.6%
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Overall Response Rate Results
Aldoxorubicin
Doxorubicin
2.4%
0%
Partial Response
19.3%
5.0%
Overall Response Rate
21.7%
5.0%
0%
0%
Partial Response
23.8%
0%
Overall Response Rate
23.8%
0%
Scans Read by Investigator
Complete Response
Scans Read by Central Lab
Complete Response
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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:
% Deaths
% Lost to
F/U
% Still
Followed
Aldoxorubicin
42
19
39
Doxorubicin
55
18
27
 Higher % deaths and lower % still being followed in
doxorubicin-treated subjects.
 Lower % deaths and higher % still being followed in
aldoxorubicin-treated subjects.
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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
PFS (months)
8.4
4.7
7.4
4.6
P value
ORR
0.0004
21.7%
0.003
5.0%
26.5%
13.6%
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Grade 3/4 TEAEs
Aldoxorubicin
Doxorubicin
N=83
N=40
(%)
(%)
40
20
Neutropenic fever
15.7
17.5
Thrombocytopenia
6
5
13.2
20
7.2
0
10.8
2.5
6.0
5.0
Event
Neutropenia
Anemia
Nausea/vomiting
Mucositis
Fatigue/weakness
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Cardiac Evaluation
Aldoxorubicin
Doxorubicin
% subjects with ≥15% decrease in
LVEF
11%
22%
% subjects with ≥15% increase in
LVEF
15%
3%
% subjects with ≤50% of expected
value
0%
9.4%
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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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Aldoxorubicin Clinical Development
Program
Aldoxorubicin
Preclinical
Phase 1
2nd-line Soft Tissue Sarcoma (STS)
Phase 3 on-going
1st- Line Soft Tissue Sarcoma
Phase 2b on-going
Glioblastoma Multiforme (GBM)
Phase 2 on-going
Kaposi’s Sarcoma
Phase 2 on-going
Small Cell Lung Cancer
Phase 2b to start 2H 2014
Pharmacokinetic Study
Phase 1 completed
Combo with gemcitabine
Ph 1b in planning
Combo with ifosfamide
Ph 1b in planning
Phase 2
Phase 3
Top-line Data
announced
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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 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
CT Scans every 6 weeks
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Ending Remark
 Aldoxorubicin has the potential to replace
doxorubicin in the chemotherapy
armamentarium to treat both adult and pediatric
cancers.
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