A PHASE II STUDY OF NANOPARTICLE ALBUMINBOUND (NAB) PACLITAXEL IN THE TREATMENT OF
PATIENTS WITH UNRESECTABLE OR METASTATIC
SARCOMA
James E. Butrynski1, Rangarajan Nadadur2, Thierry Jahan3, Victoria Chua4, Claire Bautista Lazaro4, Sant Chawla4
1. Dana-Farber Cancer Institute, Boston, MA USA 2. Massachusetts Institute of Technology, Boston, MA USA
3. University of California at San Francisco, CA USA 4. Sarcoma Center, Santa Monica, CA USA
INTRODUCTION
•nab-Paclitaxel is a novel biologically interactive, albuminbound Paclitaxel combining a protein with a
chemotherapeutic agent in a particle form. In principle,
this composition provides a novel approach of increasing
intra-tumoral concentration of the drug by a receptormediated transport process allowing transcytosis across
the endothelial cell wall. This albumin-specific receptor
mediated process involves the binding of a specific
receptor (gp60) on the endothelial cell wall, resulting in
activation of a protein caveolin-1, which initiates an
opening in the endothelial wall with formation of caveolae,
with transport of the albumin bound chemotherapeutic
complex via these caveolae to the underlying tumor
interstitium. A protein specifically secreted by the tumor
(SPARC) binds and entraps the albumin, allowing release
of the hydrophobic drug to the tumor cell membrane.
Transport of nab-Paclitaxel via this gp-60/caveolin1/caveolae/SPARC pathway potentially increases intratumoral concentration of drug while reducing toxicity to
RESULTS (2)
TOXCITY
•3 deaths on trial all due to disease progression
•grade 4 neutropenia (2)
•grade 3 neutropenia (3)
•grade 3 anemia (1)
•grade 3 hypocalcemia (1)
•grade 3 hyponatremia (1)
•grade 3 hyperglycemia (1)
RESPONSE
15 assessable patients
•Stable Disease (SD) 3 subtypes included ESS, LMS
and EMC.
•ESS patient achieved “clinical benefit” as defined in
this trial.
•LMS and EMC had SD of duration less than 6
months
•Progressive Disease (PD) 12.
normal tissue.
•One patient withdrew consent after one cycle.
•There is a need to identify new active agents with a high
probability to target the tumor to improve overall survival
for sarcoma patients.
•No patients with angiosarcoma or other vascular
tumor subtypes were entered on trial.
•The goal of this trial is to explore the activity of nabPaclitaxel for patients with sarcoma.
OBJECTIVES
PRIMARY OBJECTIVE
•To determine the clinical benefit rate by modified RECIST
(CR, PR or SD for 6 months) of nab-Paclitaxel in patients
with unresectable or metastatic soft tissue or bone
sarcoma
SECONDARY OBJECTIVES
•To assess safety and tolerability of nab-Paclitaxel
•To assess duration of response
METHODS
•This single center (Sarcoma Center, Santa Monica, CA
USA) study utilized a Simon two-stage design.
•No prior paclitaxel was allowed.
•Eligible unresectable or metastatic sarcoma patients who
underwent informed consent were treated with nab
Paclitaxel 150mg/m2 IV on day 1,8,15 every 28 days.
•Tumor assessments every 2 cycles
•All patients who receive at least one dose of nabpaclitaxel were evaluable for response and toxicity
•Toxicity was monitored throughout treatment
RESULTS (1)
•19 patients were enrolled and treated.
PATIENT CHARACTERISTICS
•M:F 12:7
•ECOG PS 0:1 1:18
•median age 48 years (range 26-81 years)
•Median number of prior regimens 4 (range 1-8)
DIAGNOSES ENROLLED
•Malignant Fibrous Histiocytoma (MFH) (4)
•Leiomyosarcoma (LMS) (3)
•Osteosarcoma (OS) (3)
•Extraskeletal Myxoid Chondosarcoma (EMC) (2)
•Synovial Sarcoma (SS) (2)
•Endometrial Stromal Sarcoma (ESS) (1)
•Peripheral Neuroectodermal Tumor (PNET) (1)
•Chondrosarcoma (CS) (1)
•Myxoid Liposarcoma (MLS) (1)
•Pleomorphic Sarcoma (PS) (1)
CONCLUSIONS
•Nab-Paclitaxel has some activity in ESS, LMS, EMC
•Acceptable safety and tolerability
•Further study in ESS, LMS, EMC is warranted
•Further study in sarcomas of the vascular tumor
subtype (Angiosarcoma, Epithelioid
hemangioendothelioma) should be considered
FUTURE DIRECTION
•Clinical studies have shown that upregulation of both
caveolin-1 and SPARC (secreted protein, acidic, rich in
cysteine) are associated with progression of cancer
Interstitial accumulation of albumin is facilitated by
SPARC. Hawkins and colleagues have reported that
tumor SPARC levels were highly associated with
treatment responses in patients with SCCHN receiving
nab-Paclitaxel
•Assesment of SPARC protein expression from archival
tumor tissue and correlate to response
REFERENCES
•Desai N, et al (2006). Increased Antitumor Activity,
Intratumor Paclitaxel Concentrations and Endothelial Cell
Transport of Cremophor-Free, Albumin-Bound Paclitaxel,
ABI-007 Compared with Cremophor-Based Paclitaxel. Clin
Cancer Res; 12(4): 1317-1324
•Olawaiye AB,et al (2008) Epithelioid Angiosarcoma of the
Uterus: A Review of Management. Arch Gynecol Obstet
278(5): 401-404
•Hawkins, M, et al. Experience with ABI-007 administered
by intra-arterial infusion to patients with cancer of the head
and neck. In: 23rd Annual Chemotherapy Foundation
Symposium, 2005, pp. Abstract #25
ACKNOWLEDGEMENTS
The authors wish to acknowledge the patients and families
who participated in this study and to Abraxis for financial
support for this study.