1. A Randomized Phase 2b Study Comparing Treatment with Aldoxorubicin Versus Doxorubicin First Line in Patients
with Advanced Soft Tissue Sarcomas
Sant P. Chawla1, M.D., Zsuzsanna Pápai, M.D.2, Guzel Mukhametshina, M.D.3, Kamalesh Sankhala, M.D.4, Mamed Aliev, M.D.5, Kennith Khamly, M.D.6, Leonid Vasylyev, M.D.7, Rajnish Nagarkar, M.D.8,
Kristen Ganjoo, M.D.9, Scott Wieland, Ph.D.10, and Daniel Levitt, M.D., Ph.D.10
1Santa Monica, CA, USA; 2Budapest, Hungary; 3Kazan, Russia; 4San Antonio, Texas, USA; 5Moscow, Russia; 6Victoria, Australia; 7Kharkiv, Ukraine; 8Maharashtra, India; 9Stanford, CA; 10CytRx Corp., USA.
Abstract
OBJECTIVE: Doxorubicin is the only approved chemotherapy for the treatment of most
advanced soft tissue sarcomas. Aldoxorubicin consists of doxorubicin attached to an
acid-sensitive linker that binds covalently and completely to circulating serum albumin in
minutes. In this phase 2b study we compared the efficacy and safety of aldoxorubicin to
doxorubicin as first line treatment for patients with advanced soft tissue sarcomas.
METHODS: This multicenter, international, open label trial was initiated in January,
2012. Approximately 120 patients ages 18 to 80 with histologically confirmed
metastatic, locally advanced or unresectable soft tissue sarcomas are randomized 2:1
to receive either 350 mg/m2 aldoxorubicin (260 mg/m2 doxorubicin equivalents) or 75
mg/m2 doxorubicin i.v. every 3 weeks for up to 6 cycles. No prior chemotherapy except
for adjuvant chemotherapy (up to 225 mg/m2 total doxorubicin) is permitted.
Tumor response by CT is being monitored every 6 weeks until end or completion of
treatment, 2 months following the end of treatment, then every 3 months until tumor
progression or withdrawal from the study. The primary endpoint is progression-free
survival for each treatment group. Secondary endpoints include overall survival, tumor
response and PFS at 4 and 6 months. A blinded, independent central radiology review
is performed for each scan. RESULTS: As of June 26, 2013 107 patients had been
randomized (aldoxorubicin 72: doxorubicin 35). 62 patients were still active
(aldoxorubicin 47: doxorubicin 15). 41 patients who received aldoxorubicin had
completed at least 4 cycles of therapy and 31 patients 6 cycles. 16 patients treated with
aldoxorubicin received at least 4 cycles and 8 patients had received 6 cycles. 8
objective responses were documented for patients in the aldoxorubicin arm and 22
patients had ongoing stable disease. For doxorubicin-treated patients, there are no
objective responses and 6 patients had stable disease. The major grade 3 or 4 adverse
event has been neutropenia. The study is ongoing with final enrollment expected by late
third quarter. CONCLUSION: Aldoxorubicin can be administered at doses greater than
3 1/2 x the standard doxorubicin dose with fewer systemic side effects. A higher
percentage of patients receiving aldoxorubicin are still active, have received at least 4
or 6 cycles of treatment and have a greater number of tumor responses and stable
disease. Preliminary results from the study should be available before the end of 2013.
Structure of Aldoxorubicin
Acid-sensitive
bond
O
OH
O
O
N
C
NH
N
Key Eligibility Criteria
Albumin-binding
group
Age between 15-80 years (US only), and 18-80 (ROW), male or
female.
Adjuvant or neoadjuvant chemotherapy (including doxorubicin) allowed
if no tumor recurrence for at least 12 months since the last
measurement, beginning or end of last chemotherapy.
O
CH2OH
OH
OCH3 O
OH
CH3
Histologically or cytologically confirmed, locally advanced,
unresectable, and/or metastatic soft tissue sarcoma of intermediate or
high grade.
OO
HO
NH2
Doxorubicin, the clinical
standard
Prior exposure to <3 cycles or <225
Doxil® cumulative dose.
Proposed Mechanism of Action
mg/m2
of either doxorubicin HCl or
Subject Status (as of October 16, 2013)
Aldoxorubicin
Screened, n
Screen Failure, n (%)
83
40
Thrombocytopenia
2
0
11 (28)
Mucositis
2
2
Discontinued, n (%)
47 (57)
29 (73)
Leucopenia
2
0
Completed Cycle 4, n
59
22
Vomiting
3
0
Completed Cycle 6, n
45
14
*number of subjects; #1 death
Aldoxorubicin is a prodrug of the anticancer agent doxorubicin which is
derivatized at its C-13 keto-position with a thiol-binding spacer molecule (
6-maleimidocaproic acid hydrazide).
Aldoxorubicin is quantitatively and selectively bound to the cysteine-34
position of endogenous albumin within a few minutes. The reaction follows
second-order kinetics.
Aldoxorubicin was superior to free doxorubicin in several human tumor
xenograft models and in low dose combination studies.1,2
Toxicological studies in mice, rats, and dogs demonstrated a 3- to 5-fold
increase in the MTD, moderate and reversible myelosuppression, no liver
toxicity and immunotoxicity, and no new toxicity compared to doxorubicin.3
Aldoxorubicin is significantly less cardiotoxic in a chronic rat model when
compared to doxorubicin at an equitoxic dose.4
Dose density of doxorubicin is important for response in sarcoma.
Doxorubicin is limited to only 75-90 mg/m2 due to toxicity.
30
0 (0)
0 (0)
15 (22.1)+
0 (0)
31 (45.6)
15 (50)
Progressive Disease, n (%)
22 (32.4)
15 (50)
*Data from blinded central imaging vendor;
7
Hungary
20
8
Russia
12
N
India
11
Australia
12
+p=0.004
compared to doxorubicin
30
Romania
Disease Progression (as of Sept. 27, 2013)*
Characteristics
Aldoxorubicin
Tumor
cells
Doxorubicin
Primary
To evaluate the progression-free survival in subjects with metastatic,
locally advanced, or unresectable soft tissue sarcomas.
Secondary
To evaluate the overall survival, progression-free survival at 4 and 6
months, and objective response rate (ORR; RECIST 1.1 criteria).
To evaluate the treatment-related toxicities in this subject population.
Study Design
Aldoxorubicin was administered at 350 mg/m2 (260 mg/m2 doxorubicin
equivalents) IV on Day 1 every 21 days for up to 6 consecutive cycles
compared to doxorubicin administered at 75 mg/m2 for up to 6
consecutive cycles. Subjects were randomized 2:1 to received
aldoxorubicin or doxorubicin.
Tumor response was monitored every 6 weeks from Cycle 1-Day 1
during treatment, at End of Treatment, 2 months following the End of
Treatment and then every 3 months until disease progression.
Safety assessments including adverse events, physical exam, serum
chemistry, CBC, urinalysis, and ECG were performed at each visit.
Cardiac function was assessed using either MUGA or cardiac
ultrasound.
18
≥ 20% ↑ in Target Lesions
17 (50%)**
12 (66.7%)
≥ 20% ↑ in Non-target Lesions
10 (29.4%)
5 (27.8%)
7 (20.6%)
1 (5.6%)
*Data from central imaging vendor; **n (%)
Linker releases the drug payload
due to acidic environment of the tumor
Objectives
34
New Lesion(s)
Background
Aldoxorubicin
Doxorubicin
68
Stable Disease, n (%)
% of Total
Enrolled
Ukraine
Recent estimates indicate that there will be 11,410 new cases of soft tissue
sarcomas diagnosed in the United States in 2013, with almost 4,390 deaths.
Doxorubicin, either alone or in combination with ifosfamide, is still considered
the mainstay chemotherapeutic agent for the treatment of advanced,
unresectable tumors.
In a phase 1 study, good objective responses (38.5%), prolonged stable
disease (53.8%), and tumor shrinkage (61.5%) were demonstrated in
chemotherapy relapsed or refractory soft tissue sarcoma patients treated with
aldoxorubicin. [2012 ASCO]
A human PK study showed that aldoxorubicin has a relatively long circulating
half-life, narrow volume of distribution, and slow clearance. Circulating free
doxorubicin was <2% of total doxorubicin measured. [2013 ESMO]
Aldoxorubicin
Partial Response, n (%)
USA
Tumor
cells
Patient Characteristics
Characteristics
2
36 (43)
Characteristics
Geographic Distribution
Country
2
5
Active, n (%)
Randomized and Dosed, n
Complete Response, n (%)
Albumin transports
drug to the tumor
10
Anemia
14 (10)
N
Aldoxorubicin is
infused into
the patient
Aldoxorubicin* Doxorubicin*#
Febrile neutropenia
140
Best Response (as of Sept. 27, 2013)*
ECOG performance status 0-2.
Life expectancy >12 weeks.
Linker rapidly binds
to cysteine-34
residue of albumin
in the blood stream
Serious Adverse Events (treatment-related)
Doxorubicin
Conclusions
• Patients treated with aldoxorubicin demonstrate significantly
higher response rates than subjects treated with doxorubicin
(blinded review).
• Higher percentage of aldoxorubicin patients received 4 (59
patients, 1000 mg/m2 doxorubicin equivalents) and 6 (45
patients, 1500 mg/m2 doxorubicin equivalents) cycles of
treatment with no clinically significant reduction in cardiac
function.
• Similar percentages of aldoxorubicin and doxorubicin patients
experienced neutropenic fever.
• Higher percentage of aldoxorubicin patients had grade 3 or 4
thrombocytopenia, mucositis or nausea or vomiting.
• Tumor responses and PFS data are still being collected.
Cardiac Evaluation
Aldoxorubicin
Doxorubicin
Aldoxorubicin
Doxorubicin
83
40
% subjects with ≥15% decrease in LVEF:
11%
22%
Age, median (range)
52.5 (22-76)
56.1 (26-78)
% subjects with ≥15% increase in LVEF:
15%
3%
Male / Female, n (%)
38 (46) / 45 (54)
18 (45) / 22 (55)
% subjects with <50% of expected value:
0%
9.4%
61 (74)
32 (80)
1 (1)
1 (2.5)
Asian
16 (19)
6 (15)
Other
5 (6)
1 (2.5)
N
Race, n (%)
Caucasian
Black or African American
Grade 3/4 Treatment Emergent Adverse Events
(regardless of relationship)
Aldoxorubicin
0-1
2
Completed Cycles, median (range)
Doxorubicin
N=83
N=40
No. (%)
No. (%)
ECOG, n (%)
80 (25)
37 (92.5)
3 (75)
3 (7.5)
Event
Gr. 3
Gr. 4
Gr. 3
Gr. 4
6 (1-6)
4 (1-6)
Neutropenia
14 (17)
9 (11)
2 (5)
3 (8)
81
38
Neutropenic fever
4 (5)
8 (10)
5 (13)
1 (3)
Leiomyosarcomas, n (%)
24 (30)
11 (29)
Thrombocytopenia
4 (5)
2 (2)
0 (0)
14 (17)
5 (13)
Anemia
2 (2)
2 (2)
9 (23)
2 (5)
Fibrosarcoma, n (%)
11 (14)
4 (11)
Leucopenia
4 (5)
4 (5)
0 (0)
2 (5)
6 (7)
4 (11)
Nausea/vomiting
5 (6)
0 (0)
0 (0)
0 (0)
25 (32)
14 (36)
Mucositis
7 (8)
0 (0)
1 (3)
0 (0)
1. Kratz F, Beyer U. Serum proteins as drug carriers of anticancer agents: a review.
Drug Delivery. 1998;5:281-299.
2. Kratz F, Azab S, et al. Combination therapy of doxorubicin and the acid-sensitive
albumin-binding prodrug of doxorbucin INNO-206 induces complete regressions in
a xenograft pancreatic carcinoma model demonstrating excellent tolerability.
AACR, 2012.
3. Kratz F, Ehling G, Kauffman H. Acute and repeat-dose toxicity studies of the
(6-maleimidocaproyl)hydrazone derivative of doxorubicin (DOXO-EMCH), an
albuminbinding prodrug of the anticancer agent doxorubicin. Human Exp. Toxicol. 2007;1935.
4. Lebrecht D, Geist A, Ketelsen U, et al. The 6-maleimidocaproyl hydrazone
derivative of doxorubicin (DOXO-EMCH) is superior to free doxorubicin with respect
to cardiotoxicity and mitochondrial damage. Int J Cancer. 2007;120:927-934.
1 (3)
Liposarcoma, n (%)
References
Unconfirmed Histopathology, N
Synovial sarcoma, n (%)
Others, n (%)
Contact Details
Sant P. Chawla, M.D.
Sarcoma Oncology Center
2811 Wilshire Blvd., Suite 414
Santa Monica, CA 90403
(310) 552-9999 – phone (310) 201-6685 – fax
E-mail santchawla@aol.com
www.sarcomaoncology.com