A PHASE II STUDY OF NANOPARTICLE ALBUMIN-BOUND (NAB) PACLITAXEL IN THE TREATMENT OF PATIENTS WITH UNRESECTABLE OR METASTATIC SARCOMA

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A PHASE II STUDY OF NANOPARTICLE ALBUMIN-BOUND
(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
RESULTS (2)

• nab-Paclitaxel is a novel biologically
  interactive, albumin-bound 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
  receptor-mediated 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/caveolin-1/caveolae/SPARC pathway
  potentially increases intra-tumoral concentration
  of drug while reducing toxicity to normal tissue.
  
• There is a need to identify new active agents
  with a high probability to target the tumor to
  improve overall survival for sarcoma patients.
• The goal of this trial is to explore the activity
  of nab-Paclitaxel for patients with sarcoma.

• 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.
• One patient withdrew consent after one cycle.
• No patients with angiosarcoma or other vascular
  tumor subtypes were entered on trial.

CONCLUSIONS
OBJECTIVES

• 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

• 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

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

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
  nab-paclitaxel were evaluable for response and
  toxicity
• Toxicity was monitored throughout treatment

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

RESULTS (1)

• 19 patients were enrolled and treated.
• PATIENT CHARACTERISTICS
• MF 127
• ECOG PS 01 118
• 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)

ACKNOWLEDGEMENTS
The authors wish to acknowledge the patients and
families who participated in this study and to
Abraxis for financial support for this study.